# Vascular homeostasis in suicidal behavior: from molecular mechanisms to clinical implications

Aiste Lengvenyte, Philippe Courtet

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Aiste Lengvenyte, Philippe Courtet. Vascular homeostasis in suicidal behavior: from molecular mechanisms to clinical implications. Biological Psychiatry, 2025, Online ahead of print. 10.1016/j.biopsych.2025.06.012. hal-05140660

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# Vascular Homeostasis in Suicidal Behavior: From Molecular Mechanisms to Clinical Implications

Aiste Lengvenyte and Philippe Courtet

## ABSTRACT

Suicidal behaviors (SBs) remain a major global health challenge, reflecting persistent gaps in understanding their neurobiological underpinnings. The scarcity of validated biological markers for diagnosis, prediction, or treatment response impedes clinical progress. Emerging evidence implicates vascular dysregulation as a contributing factor in the pathophysiology of SBs. In this review, we critically synthesize findings from clinical and preclinical studies to explore how disruptions in vascular homeostasis, including endothelial integrity, blood-brain barrier (BBB) permeability, platelet function, and microvascular flow, are associated with SB and related phenotypes. Epidemiological and genetic data further highlight shared vulnerability between SBs and cardiovascular or neurovascular conditions. Additionally, individuals with SBs exhibit signs of increased BBB permeability, platelet activation, nitric oxide dysregulation, altered kynurenine metabolism, elevated MMP-9 activity, and white matter hyperintensities. These vascular disturbances may promote a proinflammatory and oxidative environment that impairs neuroplasticity, thereby heightening vulnerability to SBs through cognitive and emotional dysregulation. Emerging molecular indicators of vascular dysfunction, such as claudin-5, thrombospondins, platelet-derived growth factors, and components of the nitric oxide system, have shown potential for improving diagnosis and guiding therapeutic development, although further replication is needed. While the current evidence remains preliminary and subject to limitations discussed herein, vascular dysfunction may serve as a dynamic indicator of both acute suicide risk and longer-term susceptibility. This review integrates vascular homeostasis into the broader biological framework of SBs, alongside stress-response pathways, inflammation, and neural dysfunction, offering novel insights into SB pathophysiology and paving the way for developing targeted diagnostic tools and interventions.

https://doi.org/10.1016/j.biopsych.2025.06.012

Suicidal behaviors (SBs) are transdiagnostic and remain a pressing global health concern despite substantial investments in prevention. Interventions such as access restriction, public education, school-based programs, psychotherapy, and treatment of psychiatric disorders have shown limited efficacy, leaving suicide rates unacceptably high (1). Biological treatments with potential antisuicidal effects, such as lithium, ketamine, clozapine, and electroconvulsive therapy, are underutilized. In particular, lithium's declining use may reflect knowledge gaps in both its mechanisms and the broader pathophysiology of SBs (2).

Although SBs have been linked to various biological correlates, including inflammation, stress-response dysregulation, neurotransmitter imbalances, and brain structural and functional anomalies (3), a more integrated understanding is essential to improve diagnostics and therapeutics. Vascular homeostasis, encompassing endothelial integrity, blood-brain barrier (BBB) permeability, platelet function, and microvascular flow, has traditionally been central to cardiovascular health but peripheral in psychiatric research (4). Emerging data suggest that vascular disruptions may contribute significantly to SB neurobiology (5,6). SBs also co-occur with cardiovascular disorders, sharing genetic and environmental risk factors

(7,8). Subtle vascular disturbances can precede cardiovascular and neurovascular disease and disrupt neural activity, neurotransmission, and stress response systems—processes that have been implicated in SBs. Recent studies have associated SBs with indices of vascular homeostasis dysregulation, including increased BBB permeability, platelet activation, nitric oxide (NO) imbalance, altered kynurenine metabolism, elevated MMP-9, and white matter hyperintensities (WMHs) (9–13).

In this review, we integrate vascular biology into the framework of SBs, focusing on how vascular homeostasis disruptions may contribute to suicide risk. We examine clinical evidence that links vascular health to SBs, explore preclinical models of stress-induced vascular dysfunction, and review biological correlates of vascular dysregulation in SBs. By emphasizing shared mechanisms among vascular disruption, inflammation, and SBs, this framework supports precision psychiatry strategies that target neurovascular health to mitigate suicide risk.

## SBs AND VASCULAR HEALTH

Emerging evidence reveals a more intricate relationship between brain and vascular health than was previously recognized. A large imaging-genetic study found significant
correlations between heart and brain morphology even after adjusting for anthropometric and lifestyle factors (14). Individuals with stress-related conditions and a history of suicide attempt (SA) show an increased risk of cardiovascular events, while existing cardiovascular disease appears to heighten suicide risk (8,15). In a case-control study, coronary heart disease independently elevated suicide risk in women even after accounting for depression (16).

The postdischarge period from psychiatric hospitalization is a well-known window of elevated suicide risk. However, a meta-analysis of mortality studies found that vascular-related deaths outnumbered suicide deaths in this group (17). Both SBs and cardiovascular/neurovascular disorders are increasingly conceptualized as stress related, with overlapping biological mechanisms. Psychosocial stress has consistently been linked to increased risk of SBs as well as cardiovascular and neurovascular events (18,19).

Epidemiological data underscore these associations. For example, Lithuania, which once reported the world's highest suicide rates, also showed a cardiovascular mortality rate in men up to 4 times higher than in neighboring Sweden. Low socioeconomic status in Lithuanian men correlated with high baseline cortisol and blunted stress response—both of which are risk factors for SBs (20,21). In the United States, rising midlife deaths from suicide and cardiometabolic diseases have been partially attributed to psychopathology that begins in adolescence (22).

Allostatic load, an index of cumulative stress that integrates metabolic, cardiovascular, and inflammatory markers, has been associated with increased suicide risk, especially in men and younger populations (23). Low socioeconomic status, a significant contributor to chronic stress, has been linked to arterial inflammation (24). Genetic studies support this overlap; genome-wide association studies (GWASs) have shown polygenic links among loneliness, severe mental illness, and cardiovascular disease, highlighting shared loci (7). Notably, a history of SA may itself function as a chronic psychosocial stressor, contributing to sustained sympathetic activation (25).

## SHARED RISK FACTORS WITH CARDIOLOGY AND NEUROLOGY

Tobacco use is a well-established modifiable risk factor for cardiovascular, neurovascular, and suicide-related mortality (26). Population-based studies have consistently associated smoking with an elevated risk of SA, independent of other mental health conditions (27). GWASs have confirmed a genetic correlation between tobacco use and SA, even after adjusting for major depressive disorder (MDD) and post-traumatic stress disorder (28), and have also linked tobacco use with genetic vulnerability to cardiovascular disease (29). Mechanistically, glutathione peroxidase-1, involved in oxidative stress, has been identified as a central gene associated with tobacco use. Smoking impairs BBB integrity by down-regulating genes critical to BBB function and induces proinflammatory leukocyte-endothelial interactions (30).

Mild traumatic brain injury, concussion, and perceived traumatic encephalopathy have also been associated with increased suicide risk, particularly among athletes (31,32). Chronic traumatic encephalopathy, a progressive neurodegenerative

disorder, involves BBB disruption, neurovascular unit impairment, microvascular injury, and accumulation of phosphorylated tau around cerebral vessels and within cortical sulci (33). Tobacco use, in turn, exacerbates posttraumatic neuroinflammation and cerebrovascular dysfunction, likely through oxidative membrane damage (34).

Registry data from Sweden show a significant, possibly causal, link between physical injuries and increased SA risk within 1 year postinjury (35). The associated healing response, which involves platelet activation and vascular remodeling, may result in persistent disruptions to vascular homeostasis. Supporting this, machine learning analyses of Veterans Affairs electronic health records identified hypoxia and vascular damage as significant predictors of suicide risk (36). Finally, hormonal contraceptives, particularly those containing synthetic progesterone, have been associated with elevated risk of SA and suicide (37). These formulations exert procoagulant effects, alter platelet function, and impact vascular endothelial activity (38).

## THERAPEUTIC DATA

Large-scale pharmacoepidemiological studies have reported promising yet mixed findings on the association between aspirin—a widely used anti-inflammatory and antiplatelet agent—and reduced risk of MDD (39). Interestingly, data from MedWatch, the Food and Drug Administration's adverse event reporting system, showed significantly fewer reports of suicidal ideation among patients using nonsteroidal anti-inflammatory drugs, such as ibuprofen, naproxen, celecoxib, and aspirin, than among patients using acetaminophen (40). Aspirin had the lowest incidence, with approximately 0.2% reporting suicidal ideation versus 0.8% for ibuprofen. While these findings are observational, they highlight the need for further investigation into aspirin's potential in mitigating suicide risk. If validated, its benefits may stem from anti-inflammatory effects or other neurobiological pathways unrelated to vascular homeostasis (41), although vascular mechanisms remain a compelling area for exploration. Additionally, selective serotonin reuptake inhibitors have been shown to reduce platelet activation, underscoring possible interactions between vascular health and psychiatric outcomes (42).

Regarding cardiovascular comorbidities, angiotensin-converting enzyme (ACE) inhibitors have been linked to lower suicide rates than angiotensin receptor blockers (ARBs) (43). Although both classes effectively lower blood pressure, they differ mechanistically: ACE inhibitors prevent the conversion of angiotensin I to angiotensin II and inhibit bradykinin degradation, thereby increasing bradykinin levels, enhancing endothelial NO production, and improving vascular function. In contrast, ARBs selectively block angiotensin II receptors without affecting bradykinin or NO pathways (44). Moreover, chronic ARB use may lead to elevated plasma angiotensin II, potentially overstimulating receptors and promoting vasoconstriction, fibrosis, and hypertrophy.

## BBB PERMEABILITY

### Linking Peripheral and Central Inflammation in SBs

Increasing evidence suggests that peripheral immune activation and neuroinflammation interact bidirectionally, potentially contributing to the pathophysiology of SBs. Individuals with
SBs show elevated levels of both systemic and central inflammatory markers (3). Inflammatory processes can disrupt BBB integrity, thereby increasing BBB permeability and allowing peripheral immune mediators to enter the central nervous system, exacerbating synaptic dysfunction, neuronal damage, and mood dysregulation (45).

Clinical studies have reported indices of BBB dysfunction in SBs. Suicide attempters show elevated cerebrospinal fluid (CSF)-to-serum albumin ratios, indicating increased BBB permeability (46). One study found that CSF levels of hyaluronic acid were correlated with these albumin ratios in suicide attempters, further implicating BBB disruption in SBs (12). Postmortem research reinforces these findings: Individuals who died by suicide showed more than twice the density of macrophage-surrounded vessels in dorsal anterior cingulate cortex white matter, as well as upregulated genes involved in monocyte recruitment (47). Glial dysfunction has also been implicated. Suicide decedents with depression exhibited impaired astrocyte-oligodendrocyte communication in the anterior cingulate cortex, with reduced expression of connexins and associated proteins, likely compromising myelination, neurovascular coupling, and BBB integrity (48).

## BBB Damage and Stress Response

While SBs cannot be fully modeled in animals, the stress-diathesis model emphasizes how interactions between pre-disposition and chronic or acute stress drive suicide risk (49). Accordingly, preclinical models of stress-related biology offer indirect but valuable insights.

Chronic stress disrupts endothelial BBB function in mice, increasing central nervous system penetration of circulating proteins and inducing anxiety- and depression-like behaviors (5,50). Claudin-5, a tight junction protein essential for BBB integrity, regulates paracellular transport and cytokine exclusion. Conditional claudin-5 knockdown heightens BBB permeability and triggers microglial and astrocytic reactivity, amplifying neuroinflammation (51). In female mice, social and variable stress reduces prefrontal claudin-5 expression, increases soluble E-selectin levels, and produces morphological changes that resemble those in women with MDD. Experimental disruption of prefrontal BBB integrity in female mice induces anxiety- and depression-like phenotypes (5). Similarly, in males, stress reduces claudin-5 expression in the nucleus accumbens, resulting in depression-like behaviors (6).

Epigenetic regulation of claudin-5 and dysregulated tumor necrosis factor (TNF)/nuclear factor-κB (NF-κB) signaling appear central to stress susceptibility and resilience—mechanisms mirrored in postmortem brains of suicide decedents with MDD (50). Stress-induced pericyte dysfunction in the prefrontal cortex also impairs BBB function, whereas restoring pericyte-endothelial signaling promotes resilience, highlighting the vascular-immune-neural interface in stress adaptation (52). Notably, not all animals exposed to stress show BBB disruption or behavioral symptoms; many maintain normal claudin-5 expression, BBB function, and social behavior (5,6,50). These individual differences may underlie vulnerability or resilience to stress-related disorders.

BBB permeability may also mediate other clinical risk factors for SBs. Sleep disturbances, a consistent predictor of

SBs, even after controlling for depression, are one such factor (53). In male mice, chronic sleep restriction reduces messenger RNA expression of tight junction proteins, including claudin-5, and increases the uptake of injected dyes in cortical and subcortical regions, reflecting BBB compromise (54). Notably, BBB permeability varies across the sleep-wake cycle, with greater efflux activity during wakefulness (55). These findings underscore how BBB dysfunction may connect stress, sleep impairment, and neuroinflammation in SBs. Figure 1 illustrates these interconnected biological pathways.

## MICROVASCULAR FLOW

### Matrix Metalloproteinase Activity

Matrix metalloproteinases (MMPs), a family of zinc-dependent proteases, are essential in vascular remodeling, BBB integrity, and angiogenesis (56). Among them, MMP-9 has attracted increasing attention for its role in cardiovascular and psychiatric disorders, including SBs. Inflammatory cytokines and NF-κB activation upregulate MMP-9, leading to BBB degradation, increased permeability, and angiogenesis. NO and MMP-9 are interrelated; NO synthase (NOS) inhibition has been shown to dose dependently increase MMP-9 levels (57).

In preclinical models, chronic corticosterone exposure elevates MMP-9 activity in the hippocampus and medial prefrontal cortex, which is correlated with behavioral despair (58). Clinically, increased MMP-9 has been observed in the blood and CSF of individuals with a history of SA (12,59). Levels vary by phenotype: One study found elevated MMP-9 in recent attempters but reduced levels in people with a history of SA (59). Postmortem findings further support context-dependent regulation. Suicide decedents who had MDD showed increased hippocampal MMP-9 (60), while those with childhood abuse histories exhibited reduced expression in the ventromedial prefrontal cortex and microglia (61). These opposing findings suggest that MMP-9 regulation is dynamic and phenotype specific. Importantly, serum MMP-9 decreases following electroconvulsive therapy, but only in treatment responders, highlighting its potential as a state-dependent therapeutic indicator (62).

### Kynurenine Pathway Dysregulation

The kynurenine pathway may link inflammation, endothelial dysfunction, and the neurobiology of SBs. Cytokines such as interleukin 6 and TNF-α activate IDO, diverting tryptophan metabolism from serotonin synthesis toward kynurenine production (63). Elevated plasma kynurenine levels have been associated with SA in individuals with MDD (13). Stress modulates this pathway: Chronic social defeat stress increases blood kynurenine and kynurenic acid levels, potentially disrupting immune balance and behavior (64), while acute stress appears to temporarily lower these metabolites, possibly as an adaptive response (65).

Kynurenine also affects vascular homeostasis directly, promoting vasodilation through activation of adenylate and guanylate cyclase (66). Elevated serum-free kynurenine has been independently associated with adverse cardiovascular outcomes (67). Additionally, infection-related interferon gamma (IFN-γ) increases platelet IDO-1 expression, further
<figure><img src="image_2.png" /><figcaption>**Figure 1.** Biological pathways linking stress to vascular homeostasis perturbance in the context of suicidal behaviors. This figure illustrates a simplified conceptual model of how biological and psychological stressors initiate a cascade of interconnected processes that disrupt vascular homeostasis, contributing to neuroimmune dysfunction, impaired cognitive and emotional regulation, and an increased risk of suicidal behaviors. Stress-induced platelet activation, mediated by thrombospondins (TSP-1, TSP-2) and platelet-derived growth factors (PDGF-AB, PDGF-BB), impacts nitric oxide synthesis and activates MMP-9. These processes collectively contribute to altered vascular tone, increased permeability, and endothelial dysfunction. Simultaneously, peripheral inflammation, driven by cortisol-induced cytokine release and kynurenine pathway activation, further impacts vascular tone and compromises endothelial function and blood-brain barrier permeability. Together, these mechanisms disrupt blood-brain barrier integrity by reducing tight junction protein expression, inducing pericyte dysfunction, and promoting endothelial cortisol resistance. This compromised vascular homeostasis facilitates cytokine and chemokine infiltration into the central nervous system, triggering neuroinflammation. These inflammatory and vascular changes may lead to synaptic dysfunction, neuronal impairment, and mood dysregulation, increasing biological rigidity and susceptibility to suicidal behaviors. (Figure created with **BioRender**.) NOS, nitric oxide synthase.</figcaption></figure>

elevating plasma kynurenine and contributing to vascular dysfunction (68).

## White Matter Hyperintensities

WMHs, visible as lesions on T2-weighted magnetic resonance imaging, are linked to ependymal loss, altered myelination, and small vessel disease (69). Strongly associated with vascular stiffness and cardiovascular remodeling, periventricular WMHs in particular show stronger correlations (70). Meanwhile, studies have reported consistent associations between WMHs and SA in affective disorders, especially MDD (9,71). Interestingly, individuals with a history of SA also show signs of accelerated epigenetic aging, which may contribute to vascular instability and the development of WMHs (72,73). WMHs have also been associated with impaired decision making—a core cognitive impairment that has been implicated in SB vulnerability (74,75).

## ENDOTHELIAL FUNCTION

The vascular endothelium, a monolayer of endothelial cells, forms the interface between the vascular lumen and underlying smooth muscle. It regulates vascular tone, permeability, hemostasis, and immune responses (76). Endothelial dysfunction is marked by reduced NO bioavailability, oxidative stress, and a proinflammatory state. Postmortem studies suggest impaired endothelial function in individuals with depression who died by suicide. One study identified altered expression of cell junction and membrane-associated genes in the habenula,

suggesting regional endothelial dysfunction linked to SBs (77). Another gene expression analysis found reduced vascular endothelial zinc finger 1 expression in suicide decedents, indicating molecular changes specific to endothelial cells (78). Additionally, decreased expression of intracellular adhesion molecule-1 in the choroid plexus of suicide decedents suggests BBB hyperpermeability (79).

Astrocytes influence BBB permeability by releasing cytokines and vascular endothelial growth factor (VEGF) during stress. People with MDD who died by suicide show reduced serum VEGF levels (80), while higher baseline VEGF levels have been associated with greater antidepressant and antisuicidal response to ketamine (81). However, an elevated VEGF:serum stem cell factor ratio has also been linked to SBs, pointing to the need for balanced VEGF signaling (82). Animal studies support VEGF's role in stress-related pathology; pharmacological inhibition of VEGF receptor 2 prevented stress-induced BBB hyperpermeability and anhedonia in mice (83). Microglia also aid BBB restoration by promoting claudin-5 expression, further emphasizing the dynamic involvement of astrocytes, endothelial cells, and microglia in neurovascular regulation (84).

Endothelial dysfunction may also link peripheral and central inflammation. Inflammatory signals may access the brain via afferent sensory pathways or through a compromised BBB, activating microglia (85). Once activated, microglia, which express toll-like receptors (TLRs), release proinflammatory cytokines in response to stress or injury. Brain endothelial cells also express TLRs and contribute to cytokine production (86). TLR dysregulation may explain links between SBs and conditions
such as infection and traumatic brain injury (33,87). Studies have reported elevated TLR gene and protein expression in the prefrontal cortex and serum of suicide decedents with depression compared with nonsuicidal individuals with depression (88). These data suggest that altered TLR signaling may amplify neuroinflammatory cascades, linking peripheral immune activation to endothelial and microglial dysfunction in SBs.

## NO PATHWAY

NO is a key vasodilator with anti-inflammatory and antioxidant effects, essential for maintaining vascular homeostasis. Impaired NO production or signaling promotes a pro-thrombotic, inflammatory, and rigid vascular state (89). NO is synthesized by 3 isoforms of NOS, expressed in endothelial and immune cells. NOS activation is triggered by shear stress and signaling molecules including bradykinin, adenosine, serotonin, and VEGF, particularly under hypoxic conditions (90). Interestingly, acute NO inhibition during stress reduces anxiety- and depressive-like behaviors in animal models (91), while chronic stress and adrenergic activation decrease NOS expression and NO availability (92).

A growing body of research implicates NO signaling in stress-related disorders (93) and broader psychopathology (94). Elevated NO levels and metabolites have been associated with SA in MDD (95,96). In borderline personality disorder, associated with elevated SA risk, increased endothelial NOS activation has also been reported (97). Genetic studies suggest that certain NOS risk genotypes may confer risk for SA, particularly in early-onset or violent subtypes (11). These findings are consistent with data linking NO pathway dysfunction to impulsive and aggressive traits often observed in these phenotypes (98,99).

The NO system is also implicated in the effects of classic antidepressants and lithium, with the latter known for its anti-suicidal properties (100,101). Notably, lithium use is associated with a reduced risk of cardiovascular and cerebrovascular disease compared with individuals with similar psychiatric diagnoses who do not receive lithium (102). These findings support targeting NO pathways as a promising therapeutic strategy for SB prevention.

## PLATELET ACTIVITY

Platelets play a key role in vascular homeostasis, linking inflammation, coagulation, and vascular repair (103). Their activation is tightly regulated under normal conditions to prevent excessive aggregation and maintain vascular integrity (104). Beyond hemostasis, platelets influence BBB dynamics and neuroinflammation, acting as a communication bridge between the brain and periphery (103). For example, they can increase BBB permeability via MMP-9 upregulation and release of serotonin, 95% of which is stored in platelets (105,106). Mental stress, a major driver of SBs, has also been associated with increased platelet activation (107).

Several studies have reported platelet abnormalities in individuals with SBs, including reduced membrane fluidity in recent suicide attempters (108) and elevated platelet counts in individuals with a history of SA (109,110). High-lethality SA has been linked to increased platelet-to-lymphocyte ratios, higher

mean platelet volume (111), and altered platelet 5-HT₂A receptor density and responsiveness (112).

Recent findings highlight the role of platelet-derived proteins—particularly thrombospondins (TSPs) and platelet-derived growth factors (PDGFs)—in SBs. TSPs, stored in platelet α-granules, regulate angiogenesis, oxidative stress, and cell signaling (113). TSP-1, a stress-responsive glycoprotein, modulates NO signaling, transforming growth factor-β activation, and neuron-astrocyte interactions (114). In preclinical models, medial prefrontal TSP-1 affects stress resilience by modulating glial communication (115). Clinically, elevated baseline TSP-1 has predicted future suicidal events independently of depressive symptoms and past SA (10). Meanwhile, TSP-2, which supports tissue repair, has been associated with recent SA and is elevated in individuals experiencing physical pain (10,116). Given the biological overlap between physical and psychological pain, which are both implicated in the suicidal process, these findings suggest that pain-related pathways may influence SBs (117). Increased pain tolerance has also been linked to the transition from suicidal ideation to action (118).

PDGFs similarly affect BBB integrity. PDGF-BB promotes endothelial-pericyte signaling, supporting vascular stabilization (119). Disrupted PDGF signaling is associated with increased BBB permeability in stress models and mood disorders (52,120). Clinically, PDGF-AB levels, such as TSP-1, have been linked to future suicidal events in patients with mood disorders (10). Elevated PDGFs have also been associated with early-life adversity and negative life events, consistent with the stress-diathesis model of SBs (121).

Together, platelet dysfunction and associated proteins illustrate the interplay between vascular homeostasis, inflammation, and stress in SBs. Importantly, vascular alterations may reflect either enduring vulnerability or acute shifts in suicide risk, supporting a dynamic framework for understanding biological changes linked to SBs.

## STRESS, CORTISOL, CATECHOLAMINES, AND NEUROVASCULAR INTEGRITY

Chronic or severe stress disrupts the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS), impairing vascular homeostasis and potentially increasing suicide risk.

Cortisol, a key HPA axis hormone, maintains vascular tone, endothelial integrity, and BBB function during acute stress (122). However, chronic stress and prolonged cortisol dysfunction are implicated in the pathophysiology of SBs. Individuals with an SA history, especially high-intent cases, often exhibit blunted cortisol reactivity and impaired dexamethasone suppression (123,124). This dysfunction likely stems from glucocorticoid receptor impairments at the receptor and signaling levels, leading to sustained cortisol abnormalities and reduced anti-inflammatory responses. Glucocorticoid receptor resistance also weakens BBB integrity by downregulating tight junction proteins (claudin-5, ZO-1, occludin) and upregulating adhesion molecules (125). In endothelial cells, glucocorticoid receptor resistance amplifies vasoconstriction, impairs vascular tone, and hampers BBB repair (126).

Concurrently, chronic SNS activation increases circulating catecholamines (norepinephrine, epinephrine), which can
<figure><img src="image_3.png" /><figcaption>**Figure 2.** Simplified illustration of key biological factors that potentially link vascular homeostasis dysfunction and suicidal behaviors. This figure provides a simplified overview of biological factors implicated in the pathophysiology of suicidal behaviors through their roles in vascular homeostasis. These factors are grouped into 4 categories to highlight distinct mechanisms: 1) platelet activity: thrombospondins, platelet-derived growth factors, and platelet activation parameters; 2) blood-brain barrier permeability: claudin-5, S100B, cerebrospinal fluid-to-serum albumin ratio, hyaluronic acid in the cerebrospinal fluid, and expression of connexins in the ACC (postmortem finding); 3) microvascular flow: NO dysregulation, KYN pathway alterations, white matter hyperintensities, and MMP-9 activity; and 4) endothelial function: VEGF signaling, TLR expression, and NO bioavailability. NO appears in 2 categories due to its pleiotropic effects on both endothelial function and vascular tone. This figure is not exhaustive but highlights biological candidates with potential translational relevance for understanding and targeting neurovascular mechanisms involved in suicidal behaviors. (Figure created with BioRender.) ACC, anterior cingulate cortex; KYN, kynurenine; NO, nitric oxide; TLR, toll-like receptor; VEGF, vascular endothelial growth factor.</figcaption></figure>

induce hypertension, oxidative stress, decreased NO bioavailability, platelet hyperreactivity, and BBB permeability (107,127). While direct links between these vascular effects and SBs are limited, the low-activity COMT Val158Met allele, which reduces catecholamine breakdown, has been associated with male-specific SA risk (128). Postmortem studies have also shown fewer locus coeruleus projections and altered prefrontal β-adrenergic binding in suicide decedents (129), and SA has been linked to dysregulated catecholamine metabolism in the CSF and plasma (130,131). Heart rate variability measures of SNS hyperactivity have been associated with endothelial dysfunction and short-term SA risk (132).

Hypertension, a risk factor for SBs (133), often arises from chronic HPA and SNS activation, reflecting allostatic overload (134). This stress-induced hypertensive state, marked by altered blood pressure dynamics (135), further compromises vascular health. It causes endothelial shear injury, increases MMP activity, and impairs BBB by disrupting tight junctions and pericyte support (136). These effects are worsened by cortisol-driven NO reduction and increased vascular resistance (137). Resulting hemodynamic stress contributes to white matter damage (138) and illustrates how stress-induced hypertension links allostatic load to endothelial dysfunction and BBB compromise, which are key facets of neurovascular vulnerability in SBs.

## AGE AND SEX CONSIDERATIONS

Age and sex critically influence vascular homeostasis and may underlie epidemiological disparities in SBs. While nonfatal SAs are more common in young females, fatal SBs disproportionately affect males and older adults (139). Aging impairs vascular health, characterized by arterial stiffening, reduced NO bioavailability, BBB decline, and increased WMHs (73,140). In females, estrogen provides vasoprotection before menopause, an advantage that diminishes postmenopause (141), possibly reflected in increased suicide risk during menstruation in younger women (142). Notably, older age and male sex are associated with lower BBB integrity (143), while women exhibit larger stress-induced blood pressure surges (144). Supporting these findings, preclinical studies have shown that chronic stress may disrupt BBB integrity more profoundly in female than male mice (5,6). Understanding these age- and sex-specific vascular profiles and their differential stress responses is essential for clarifying SB heterogeneity and guiding more targeted prevention strategies.

## CONCLUSIONS AND FUTURE DIRECTIONS

Vascular dysfunction is increasingly being recognized as a contributor to the pathophysiology of SBs. Disruptions in BBB integrity, endothelial function, and platelet activity foster a
neurovascular environment marked by inflammation, oxidative stress, and impaired neuroplasticity. Alterations such as reduced claudin-5 expression, elevated TSP-1, NO dysregulation, and increased MMP-9 activity offer mechanistic links between vascular dysregulation and SBs (6,10,12,59,95) (see Figure 2). These biological indicators, although they have not yet been clinically validated, may hold translational promise as diagnostic tools or therapeutic targets. Additional pathways, such as kynurenine metabolism, cortisol dysregulation, and WMHs, highlight how vascular changes may interact with stress and other systems to increase SB vulnerability (64,126).

Future research should prioritize longitudinal, multimodal studies to clarify the temporal course of vascular changes in SBs and evaluate their potential as biomarkers. A biomarker is defined as “a characteristic that is objectively measured as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention” (145). Validation requires precise phenotyping, standardized measures, and evidence of reliability and contextual relevance. Most reviewed factors remain promising but unvalidated.

Specificity is a key challenge. Vascular homeostasis changes, such as inflammation and kynurenine pathway activity, are not unique to SBs but also appear across various psychiatric disorders (146,147). Although, as discussed, studies have reported associations between vascular homeostasis markers and SA independent of psychiatric diagnoses, many alterations are also stress responsive, and SA itself constitutes a potent stressor. This raises a critical question: Do vascular abnormalities reflect general vulnerability to psychopathology, with SBs arising when these changes intersect with acute stress, genetic predispositions, or cognitive risk factors such as impaired decision making or do specific patterns or severities of vascular dysfunction directly increase SB risk? Addressing this requires carefully controlled studies that compare people with SBs with matched psychiatric control individuals and systems biology approaches to uncover shared and distinct pathways. Preclinical models of vascular disruption and restoration may further clarify causality and highlight therapeutic targets. Sex and age differences, both of which modulate vascular function and SB risk, should be systematically integrated into future analyses.

Therapeutic modulation of vascular homeostasis via pharmacological and behavioral interventions shows promise for SB prevention. Preliminary data suggest that vascular restoration is possible (148), but it remains unclear whether such interventions can meaningfully reduce SB risk. Bridging vascular biology and psychiatry could open new avenues for mechanistic treatments, but this will require coordinated efforts across neuroscience, vascular biology, and mental health disciplines.

## ACKNOWLEDGMENTS AND DISCLOSURES

AL is partially supported by a Young Investigator Grant from the Brain & Behavior and Research Foundation (Rosalie and Daniel Katz Family Investigator). The contents of this publication are solely the responsibility of the authors.

The authors report no biomedical financial interests or potential conflicts of interest.

## ARTICLE INFORMATION

From the Department of Emergency Psychiatry and Acute Care, Lapeyronie Hospital, Centre Hospitalier Universitaire de Montpellier, Montpellier, France

(AL, PC); Institute of Functional Genomics, University of Montpellier, National Centre for Scientific Research, French National Institute of Health and Medical Research, Montpellier, France (AL, PC); and Fondation Fonda-Mental, Créteil, France (PC).

Address correspondence to Aiste Lengvenyte, M.D., Ph.D., at aiste.lengvenyte@chu-montpellier.fr.

Received Jan 23, 2025; revised May 22, 2025; accepted Jun 12, 2025.

## REFERENCES

1. Mann JJ, Michel CA, Auerbach RP (2021): Improving suicide prevention through evidence-based strategies: A systematic review. Am J Psychiatry 178:611-624.

2. Desai Boström AE, Andersson P, Rask-Andersen M, Jarbin H, Lundberg J, Jokinen J (2023): Regional clozapine, ECT and lithium usage inversely associated with excess suicide rates in male adolescents. Nat Commun 14:1281.

3. Lengvenyte A, Conejero I, Courtet P, Olié E (2021): Biological bases of suicidal behaviours: A narrative review. Eur J Neurosci 53:330-351.

4. Humphrey JD, Schwartz MA (2021): Vascular mechanobiology: Homeostasis, adaptation, and disease. Annu Rev Biomed Eng 23:1-27.

5. Dion-Albert L, Cadoret A, Doney E, Kaufmann FN, Dudek KA, Daigle B, et al. (2022): Vascular and blood-brain barrier-related changes underlie stress responses and resilience in female mice and depression in human tissue. Nat Commun 13:164.

6. Menard C, Pfau ML, Hodes GE, Kana V, Wang VX, Bouchard S, et al. (2017): Social stress induces neurovascular pathology promoting depression. Nat Neurosci 20:1752-1760.

7. Rodevand L, Bahrami S, Frei O, Lin A, Gani O, Shadrin A, et al. (2021): Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms. Transl Psychiatry 11:3.

8. Yang J, Zeng Y, Yang H, Qu Y, Han X, Chen W, et al. (2024): Cardiovascular disease, genetic susceptibility, and risk of psychiatric disorders and suicide attempt: A community-based matched cohort study based on the UK Biobank. J Am Heart Assoc 13:e031280.

9. Grangeon MC, Seixas C, Quarantini LC, Miranda-Scippa A, Pompili M, Steffens DC, et al. (2010): White matter hyperintensities and their association with suicidality in major affective disorders: A meta-analysis of magnetic resonance imaging studies. CNS Spectr 15:375-381.

10. Lengvenyte A, Belzeaux R, Olié E, Hamzeh-Cognasse H, Sénèque M, Strumila R, et al. (2023): Associations of potential plasma biomarkers with suicide attempt history, current suicidal ideation and subsequent suicidal events in patients with depression: A discovery study. Brain Behav Immun 114:242-254.

11. Lengvenyte A, Sundaresh A, Strumila R, Boukouaci W, Wu C-L, Sugunasabesan S, et al. (2022): Combined effects of nitric oxide synthase 3 genetic variant and childhood emotional abuse on earlier onset of suicidal behaviours. Prog Neuropsychopharmacol Biol Psychiatry 119:110617.

12. Ventorp F, Barzilay R, Erhardt S, Samuelsson M, Träskman-Bendz L, Janelidze S, et al. (2016): The CD44 ligand hyaluronic acid is elevated in the cerebrospinal fluid of suicide attempters and is associated with increased blood-brain barrier permeability. J Affect Disord 193:349-354.

13. Sublette ME, Galfalvy HC, Fuchs D, Lapidus M, Grunebaum MF, Oquendo MA, et al. (2011): Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder. Brain Behav Immun 25:1272-1278.

14. Zhao B, Li T, Fan Z, Yang Y, Shu J, Yang X, et al. (2023): Heart-brain connections: Phenotypic and genetic insights from magnetic resonance images. Science 380:abn6598.

15. Shen Q, Mikkelsen DH, Luitva LB, Song H, Kasela S, Aspelund T, et al. (2023): Psychiatric disorders and subsequent risk of cardiovascular disease: A longitudinal matched cohort study across three countries. EClinicalmedicine 61:102063.

16. Webb RT, Kontopantelis E, Doran T, Qin P, Creed F, Kapur N (2012): Suicide risk in primary care patients with major physical diseases: A case-control study. Arch Gen Psychiatry 69:256-264.
17. Swaraj S, Wang M, Chung D, Curtis J, Firth J, Ramanuj PP, et al. (2019): Meta-analysis of natural, unnatural and cause-specific mortality rates following discharge from in-patient psychiatric facilities. Acta Psychiatr Scand 140:244-264.

18. Batty GD, Kivimäki M, Bell S, Gale CR, Shipley M, Whitley E, Gunnell D (2018): Psychosocial characteristics as potential predictors of suicide in adults: An overview of the evidence with new results from prospective cohort studies. Transl Psychiatry 8:22-22.

19. Santosa A, Rosengren A, Ramasundarahettige C, Rangarajan S, Gulec S, Chifamba J, et al. (2021): Psychosocial risk factors and cardiovascular disease and death in a population-based cohort from 21 low-, middle-, and high-income countries. JAMA Netw Open 4: e2138920.

20. Kristenson M, Kucinskiene Z, Bergdahl B, Orth-Gomér K (2001): Risk factors for coronary heart disease in different socioeconomic groups of Lithuania and Sweden — The LiVicordia study. Scand J Public Health 29:140-150.

21. O'Connor DB, Ferguson E, Green JA, O'Carroll RE, O'Connor RC (2016): Cortisol levels and suicidal behavior: A meta-analysis. Psychoneuroendocrinology 63:370-379.

22. Dent KR, Brennan GM, Khalifeh L, Richmond-Rakerd LS (2024): Midlife diseases of despair and cardiometabolic risk: Testing shared origins in adolescent psychopathology. Psychol Med 54:2866-2875.

23. Gou Y, Cheng S, Kang M, Zhou R, Liu C, Hui J, et al. (2025): Association of allostatic load with depression, anxiety, and suicide: A prospective cohort study. Biol Psychiatry 97:786-793.

24. Tawakol A, Osborne MT, Wang Y, Hammed B, Tung B, Patrich T, et al. (2019): Stress-associated neurobiological pathway linking socioeconomic disparities to cardiovascular disease. J Am Coll Cardiol 73:3243-3255.

25. Ortiz A, Park Y, MacLean S, Husain MI, Sanches M, Ravindran A, Mulsant BH (2024): A history of suicide attempt is associated with increased sympathetic activation in bipolar disorder. Can J Psychiatry 69:126-137.

26. Carter BD, Abnet CC, Feskanich D, Freedman ND, Hartge P, Lewis CE, et al. (2015): Smoking and mortality — Beyond established causes. N Engl J Med 372:631-640.

27. Lee PH, Tervo-Clemmens B, Liu RT, Gersten MB, Jung J-Y, Janes AC, Gilman J (2024): Use of tobacco products and suicide attempts among elementary school-aged children. JAMA Netw Open 7:e240376.

28. Docherty AR, Mullins N, Ashley-Koch AE, Qin X, Coleman JRI, Shabalin A, et al. (2023): GWAS meta-analysis of suicide attempt: Identification of 12 genome-wide significant loci and implication of genetic risks for specific health factors. Am J Psychiatry 180:723-738.

29. Toikumo S, Jennings MV, Pham BK, Lee H, Mallard TT, Bianchi SB, et al. (2024): Multi-ancestry meta-analysis of tobacco use disorder identifies 461 potential risk genes and reveals associations with multiple health outcomes. Nat Hum Behav 8:1177-1193.

30. Heldt NA, Seliga A, Winfield M, Gajghate S, Reichenbach N, Yu X, et al. (2020): Electronic cigarette exposure disrupts blood-brain barrier integrity and promotes neuroinflammation. Brain Behav Immun 88:363-380.

31. Fralick M, Sy E, Hassan A, Burke MJ, Mostofsky E, Karsies T (2019): Association of concussion with the risk of suicide: A Systematic Review and Meta-analysis. JAMA Neurol 76:144-151.

32. Grashow R, Terry DP, Iverson GL, DiGregorio H, Dairi I, Brown C, et al. (2024): Perceived chronic traumatic encephalopathy and suicidality in former professional football players. JAMA Neurol 81:1130-1139.

33. Mez J, Daneshvar DH, Kiernan PT, Abdolmohammadi B, Alvarez VE, Huber BR, et al. (2017): Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 318:360-370.

34. Durazzo TC, Abadjian L, Kincaid A, Bilovsky-Muniz T, Boreta L, Gauger GE (2013): The influence of chronic cigarette smoking on neurocognitive recovery after mild traumatic brain injury. J Neurotrauma 30:1013-1022.

35. Stephenson M, Ohlsson H, Lannoy S, Sundquist J, Sundquist K, Edwards AC (2024): Clarifying the relationship between physical

injuries and risk for suicide attempt in a Swedish national sample. Acta Psychiatr Scand 149:389-403.

36. Dhaubhadel S, Ganguly K, Ribeiro RM, Cohn JD, Hyman JM, Hengartner NW, et al. (2024): High dimensional predictions of suicide risk in 4.2 million US Veterans using ensemble transfer learning. Sci Rep 14:1793.

37. Skovlund CW, Mørch LS, Kessing LV, Lange T, Lidegaard Ø. (2018): Association of hormonal contraception with suicide attempts and suicides. Am J Psychiatry 175:336-342.

38. Williams JS, MacDonald MJ (2021): Influence of hormonal contraceptives on peripheral vascular function and structure in premenopausal females: A review. Am J Physiol Heart Circ Physiol 320:H77-H89.

39. Glaus J, Vandeleur CL, Lasserre AM, Strippoli M-PF, Castelao E, Gholam-Rezaee M, et al. (2015): Aspirin and statin use and the subsequent development of depression in men and women: Results from a longitudinal population-based study. J Affect Disord 182:126-131.

40. Lehrer S, Rheinstein PH (2019): Nonsteroidal anti-inflammatory drugs (NSAIDs) reduce suicidal ideation and depression. Discov Med 28:205-212.

41. Berk M, Dean O, Drexhage H, McNeil JJ, Moylan S, O'Neil A, et al. (2013): Aspirin: A review of its neurobiological properties and therapeutic potential for mental illness. BMC Med 11:74.

42. Chu C-S, Chou P-H, Lin C-H, Cheng C, Tsai C-J, Lan T-H, et al. (2016): Use of selective serotonin reuptake inhibitors and risks of stroke in patients with obsessive compulsive disorder: A population-based study. PLoS One 11:e0162239.

43. Mamdani M, Gomes T, Greaves S, Manji S, Juurlink DN, Tadrous M, et al. (2019): Association between angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and suicide. JAMA Netw Open 2:e1913304.

44. Lévy BI, Mourad JJ (2022): Renin angiotensin blockers and cardiac protection: From basis to clinical trials. Am J Hypertens 35:293-302.

45. Librizzi L, de Cutis M, Janigro D, Runtz L, de Bock F, Barbier EL, Marchi N (2018): Cerebrovascular heterogeneity and neuronal excitability. Neurosci Lett 667:75-83.

46. Bayard-Burfield L, Alling C, Blennow K, Jönsson S, Träskman-Bendz L (1996): Impairment of the blood-CSF barrier in suicide attempters. Eur Neuropsychopharmacol 6:195-199.

47. Torres-Platas SG, Cruceanu C, Chen GG, Turecki G, Mechawar N (2014): Evidence for increased microglial priming and macrophage recruitment in the dorsal anterior cingulate white matter of depressed suicides. Brain Behav Immun 42:50-59.

48. Tanti A, Lutz P-E, Kim J, O'Leary L, Théroux J-F, Turecki G, Mechawar N (2019): Evidence of decreased gap junction coupling between astrocytes and oligodendrocytes in the anterior cingulate cortex of depressed suicides. Neuropsychopharmacology 44:2099-2111.

49. van Heeringen K (2012): Stress-diathesis model of suicidal behavior. In: Dwivedi Y, editor. The Neurobiological Basis of Suicide. Boca Raton, FL: CRC Press/Taylor & Francis. Available at: http://www.ncbi.nlm.nih.gov/books/NBK107203/. Accessed August 12, 2024.

50. Dudek KA, Dion-Albert L, Lebel M, LeClair K, Labrecque S, Tuck E, et al. (2020): Molecular adaptations of the blood-brain barrier promote stress resilience vs. depression. Proc Natl Acad Sci USA 117:3326-3336.

51. Vázquez-Liébanas E, Mocci G, Li W, Laviña B, Reddy A, O'Connor C, et al. (2024): Mosaic deletion of claudin-5 reveals rapid non-cell-autonomous consequences of blood-brain barrier leakage. Cell Rep 43:113911.

52. Menard C, Dion-Albert L, Cadoret A, Solano J, Kotchetkov P, Pancotti L, et al. (2024): Pericytes modulate brain vascular integrity in social stress and depression. Research Square. https://doi.org/10.21203/rs.3.rs-5060339/v1.

53. Bernert RA, Survey CL, Conwell Y, Joiner TE (2014): Association of poor subjective sleep quality with risk for death by suicide during a 10-year period: A longitudinal, population-based study of late life. JAMA Psychiatry 71:1129-1137.

54. He J, Hsuchou H, He Y, Kastin AJ, Wang Y, Pan W (2014): Sleep restriction impairs blood-brain barrier function. J Neurosci 34:14697-14706.
55. Zhang SL, Lahens NF, Yue Z, Arnold DM, Pakstis PP, Schwarz JE, Sehgal A (2021): A circadian clock regulates efflux by the blood-brain barrier in mice and human cells. Nat Commun 12:617.

56. O'Sullivan S, Medina C, Ledwidge M, Radomski MW, Gilmer JF (2014): Nitric oxide-matrix metaloproteinase-9 interactions: Biological and pharmacological significance—NO and MMP-9 interactions. Biochim Biophys Acta 1843:603–617.

57. Eagleton MJ, Peterson DA, Sullivan VV, Roelofs KJ, Ford JA, Stanley JC, Upchurch GR (2002): Nitric oxide inhibition increases aortic wall matrix metalloproteinase-9 expression. J Surg Res 104:21–21.

58. Breviario S, Senserrich J, Florensa-Zanuy E, Garro-Martínez E, Díaz Á., Castro E, et al. (2023): Brain matrix metalloproteinase-9 activity is altered in the corticosterone mouse model of depression. Prog Neuropsychopharmacol Biol Psychiatry 120:110624.

59. Elveren F, Öztürk N, Akgöl Gür ST (2024): Evaluation of MMP-9 enzyme in drug-induced suicide cases admitted to the emergency room. J Psychiatr Res 180:163–168.

60. Bijata M, Bączyńska E, Müller FE, Bijata K, Masternak J, Krzystyniak A, et al. (2022): Activation of the 5-HT7 receptor and MMP-9 signaling module in the hippocampal CA1 region is necessary for the development of depressive-like behavior. Cell Rep 38: 110532.

61. Belliveau C, Rahimian R, Fakhouri G, Hosdey C, Simard S, Davoli MA, et al. (2025): Evidence of microglial involvement in the childhood abuse-associated increase in perineuronal nets in the ventromedial prefrontal cortex. Brain Behav Immun 124:321–334.

62. Shibasaki C, Itagaki K, Abe H, Kajitani N, Okada-Tsuchioka M, Takebayashi M (2018): Possible association between serum matrix metalloproteinase-9 (MMP-9) levels and relapse in depressed patients following electroconvulsive therapy (ECT). Int J Neuro-psychopharmacol 21:236–241.

63. Schwieler L, Larsson MK, Skogh E, Kegel ME, Orhan F, Abdelmoaty S, et al. (2015): Increased levels of IL-6 in the cerebrospinal fluid of patients with chronic schizophrenia—Significance for activation of the kynurenine pathway. J Psychiatry Neurosci 40:126–133.

64. Fuertig R, Azzinnari D, Bergamini G, Cathomas F, Sigrist H, Seifritz E, et al. (2016): Mouse chronic social stress increases blood and brain kynurenine pathway activity and fear behaviour: Both effects are reversed by inhibition of indoleamine 2,3-dioxygenase. Brain Behav Immun 54:59–72.

65. La Torre D, Dalile B, de Loor H, Van Oudenhove L, Verbeke K (2021): Changes in kynurenine pathway metabolites after acute psychosocial stress in healthy males: A single-arm pilot study. Stress 24:920–930.

66. Wang Y, Liu H, McKenzie G, Witting PK, Stasch J-P, Hahn M, et al. (2010): Kynurenine is an endothelium-derived relaxing factor produced during inflammation. Nat Med 16:279–285.

67. El Chamieh C, Larabi IA, Alencar De Pinho N, Lambert O, Combe C, Fouque D, et al. (2024): Study of the association between serum levels of kynurenine and cardiovascular outcomes and overall mortality in chronic kidney disease. Clin Kidney J 17:sfad248.

68. Blick-Nitko SK, Ture SK, Schafer XL, Munger JC, Livada AC, Li C, et al. (2024): Platelet ldo1 expression is induced during Plasmodium yoelii infection, altering plasma tryptophan metabolites. Blood Adv 8:5814–5825.

69. Thomas AJ, O'Brien JT, Davis S, Ballard C, Barber R, Kalaria RN, Perry RH (2002): Ischemic basis for deep white matter hyperintensities in major depression: A neuropathological study. Arch Gen Psychiatry 59:785–792.

70. Hannawi Y, Vaidya D, Yanek LR, Johansen MC, Kral BG, Becker LC, et al. (2022): Association of vascular properties with the brain white matter hyperintensity in middle-aged population. J Am Heart Assoc 11:e024606.

71. Furnica C, Ro C, Constantin M-M, Perianu L, Rusu AC, Alexa A, Grigore T (2016): Biochemical correlates of MRI white matter hyperintensities. Revista de Chimie 67:1210–1213.

72. Lima CNC, Kovács EHC, Mirza S, Del Favero-Campbell A, Díaz AP, Quevedo J, et al. (2023): Association between the epigenetic lifespan predictor GrimAge and history of suicide attempt in bipolar disorder. Neuropsychopharmacology 48:954–962.

73. Raina A, Zhao X, Grove ML, Bressler J, Gottesman RF, Guan W, et al. (2017): Cerebral white matter hyperintensities on MRI and acceleration of epigenetic aging: The atherosclerosis risk in communities study. Clin Epigenet 9:21.

74. Rothstein A, Zhang Y, Briggs AQ, Bernard MA, Shao Y, Favilla C, et al. (2023): Impact of white matter hyperintensities on subjective cognitive decline phenotype in a diverse cohort of cognitively normal older adults. Int J Geriatr Psychiatry 38:e5948.

75. Sastre-Buades A, Alacreu-Crespo A, Courtet P, Baca-Garcia E, Barrigón ML (2021): Decision-making in suicidal behavior: A systematic review and meta-analysis. Neurosci Biobehav Rev 131:642–662.

76. Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS (2020): Nitric oxide and endothelial dysfunction. Crit Care Clin 36:307–321.

77. Kim HJ, Yoo H, Kim JY, Yang SH, Lee HW, Lee H-J, et al. (2022): Postmortem gene expression profiles in the habenulae of suicides: Implication of endothelial dysfunction in the neurovascular system. Mol Brain 15:48.

78. Piras IS, Huentelman MJ, Pinna F, Paribello P, Solmi M, Murru A, et al. (2022): A review and meta-analysis of gene expression profiles in suicide. Eur Neuropsychopharmacol 56:39–49.

79. Devorak J, Torres-Platas SG, Davoli MA, Prud'homme J, Turecki G, Mechawar N (2015): Cellular and molecular inflammatory profile of the choroid plexus in depression and suicide. Front Psychiatry 6:138.

80. Isung J, Aeinehband S, Mobarrez F, Mårtensson B, Nordström P, Asberg M, et al. (2012): Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters. Transl Psychiatry 2:e196.

81. Chen M-H, Lin W-C, Li C-T, Wu H-J, Bai Y-M, Tsai S-J, et al. (2023): Effects of low-dose ketamine infusion on vascular endothelial growth factor and matrix metalloproteinase-9 among patients with treatment-resistant depression and suicidal ideation. J Psychiatr Res 165:91–95.

82. Maes M, Zhou B, Vasupanrajit A, Jirakran K, Klomkliew P, Chanchaem P, et al. (2024): A further examination of growth factors, T helper 1 polarization, and the gut microbiome in major depression: Associations with reoccurrence of illness, cognitive functions, suicidal behaviors, and quality of life. J Psychiatr Res 176:430–441.

83. Matsuno H, Tsuchimine S, O'Hashi K, Sakai K, Hattori K, Hideše S, et al. (2022): Association between vascular endothelial growth factor-mediated blood-brain barrier dysfunction and stress-induced depression. Mol Psychiatry 27:3822–3832.

84. Haruwaka K, Ikegami A, Tachibana Y, Ohno N, Konishi H, Hashimoto A, et al. (2019): Dual microglia effects on blood brain barrier permeability induced by systemic inflammation. Nat Commun 10:5816.

85. Serna-Rodríguez MF, Bernal-Vega S, de la Barquera JAOS, Camacho-Morales A, Pérez-Maya AA (2022): The role of damage associated molecular pattern molecules (DAMPs) and permeability of the blood-brain barrier in depression and neuroinflammation. J Neuroimmunol 371:577951.

86. Deravi N, Poudineh M, Pirzadeh M, Yavarpour-Bali H, Mehrabi H, Erabi G, et al. (2022): The Yin and Yang of toll-like receptors in endothelial dysfunction. Int Immunopharmacol 108:108768.

87. Lund-Sørensen H, Benros ME, Madsen T, Sørensen HJ, Eaton WW, Postolache TT, et al. (2016): A nationwide cohort study of the association between hospitalization with infection and risk of death by suicide. JAMA Psychiatry 73:912–919.

88. Pandey GN, Rizavi HS, Bhaumik R, Ren X (2019): Innate immunity in the postmortem brain of depressed and suicide subjects: Role of toll-like receptors. Brain Behav Immun 75:101–111.

89. Niraula A, Wang Y, Godbout JP, Sheridan JF (2018): Corticosterone production during repeated social defeat causes monocyte mobilization from the bone marrow, glucocorticoid resistance, and neurovascular adhesion molecule expression. J Neurosci 38:2328–2340.

90. Deanfield JE, Halcox JP, Rabelink TJ (2007): Endothelial function and dysfunction: Testing and clinical relevance. Circulation 115:1285–1295.

91. Guan Y, Wang J, Wu X, Song L, Wang Y, Gong M, Li B (2021): Quercetin reverses chronic unpredictable mild stress-induced
depression-like behavior in vivo by involving nuclear factor-E2-related factor 2. Brain Res 1772:147661.

92. Bernatova I, Puzserova A, Balis P, Sestakova N, Horvathova M, Kralovicova Z, Zitnanova I (2018): Chronic stress produces persistent increases in plasma corticosterone, reductions in brain and cardiac nitric oxide production, and delayed alterations in endothelial function in young Prehypertensive rats. Front Physiol 9:1179.

93. Joca SRL, Sartim AG, Roncalho AL, Diniz CFA, Wegener G (2019): Nitric oxide signalling and antidepressant action revisited. Cell Tissue Res 377:45-58.

94. McNeill RV, Kehrwald C, Brum M, Knopf K, Brunkhorst-Kanaan N, Etyemez S, et al. (2022): Uncovering associations between mental illness diagnosis, nitric oxide synthase gene variation, and peripheral nitric oxide concentration. Brain Behav Immun 101:275-283.

95. Lee BH, Lee SW, Yoon D, Lee HJ, Yang JC, Shim SH, et al. (2006): Increased plasma nitric oxide metabolites in suicide attempters. Neuropsychobiology 53:127-132.

96. Vargas HO, Nunes SOV, Pizzo de Castro M, Bortolasci CC, Sabbatini Barbosa D, Kaminivi Morimoto H, et al. (2013): Oxidative stress and lowered total antioxidant status are associated with a history of suicide attempts. J Affect Disord 150:923-930.

97. MacDowell KS, Marsá MD, Buenache E, Villatoro JML, Moreno B, Leza JC, Carrasco JL (2020): Inflammatory and antioxidant pathway dysfunction in borderline personality disorder. Psychiatry Res 284:112782.

98. Hoogman M, Aarts E, Zwiers M, Slaats-Willemsen D, Naber M, Onnink M, et al. (2011): Nitric oxide synthase genotype modulation of impulsivity and ventral striatal activity in adult ADHD patients and healthy comparison subjects. Am J Psychiatry 168:1099-1106.

99. O'Leary A, Laas K, Vaht M, Kiive E, Veidebaum T, Reif A, Harro J (2020): Nitric oxide synthase genotype interacts with stressful life events to increase aggression in male subjects in a population- representative sample. Eur Neuropsychopharmacol 30:56-65.

100. Loeb E, El Asmar K, Trabado S, Gressier F, Colle R, Rigal A, et al. (2022): Nitric Oxide Synthase activity in major depressive episodes before and after antidepressant treatment: Results of a large case-control treatment study. Psychol Med 52:80-89.

101. Ostadhadi S, Norouzi-Javidan A, Nikoui V, Zolfaghari S, Moradi A, Dehpour AR (2018): Nitric oxide involvement in additive antidepressant-like effect of agmatine and lithium in mice forced swim test. Psychiatry Res 266:262-268.

102. Ponzer K, Millischer V, Schalling M, Gissler M, Lavebratt C, Backlund L (2023): Lithium and risk of cardiovascular disease, dem- entia and venous thromboembolism. Bipolar Disord 25:391-401.

103. Cognasse F, Laradi S, Berthelot P, Bourlet T, Marotte H, Mismetti P, et al. (2019): Platelet inflammatory response to stress. Front Immunol 10:1478.

104. Gupta S, Konradt C, Corken A, Ware J, Nieswandt B, Di Paola J, et al. (2020): Hemostasis vs. homeostasis: Platelets are essential for pre- serving vascular barrier function in the absence of injury or inflam- mation. Proc Natl Acad Sci U S A 117:24316-24325.

105. Cloutier N, Paré A, Farndale RW, Schumacher HR, Nigrovic PA, Lacroix S, Boilard E (2012): Platelets can enhance vascular perme- ability. Blood 120:1334-1343.

106. Wagenhäuser MU, Mulorz J, Krott KJ, Bosbach A, Feige T, Rhee YH, et al. (2024): Crosstalk of platelets with macrophages and fibroblasts aggravates inflammation, aortic wall stiffening, and osteopontin release in abdominal aortic aneurysm. Cardiovasc Res 120:417-432.

107. Koudouovoh-Tripp P, Húfner K, Egerer J, Kandler C, Giesinger JM, Sopper S, et al. (2021): Stress enhances proinflammatory platelet activity: The impact of acute and chronic mental stress. J Neuroimmune Pharmacol 16:500-512.

108. Mathew B, Srinivasan K, Pradeep J, Thomas T, Mandal AK (2018): Suicidal behaviour is associated with decreased esterified choles- terol in plasma and membrane fluidity of platelets. Asian J Psychiatry 32:105-109.

109. Cui S, Liu Z, Liu Y, Yao G, Wu Y, Li J, et al. (2023): Correlation be- tween systemic immune-inflammation index and suicide attempts in children and adolescents with first-episode, drug-naïve major

depressive disorder during the COVID-19 pandemic. J Inflamm Res 16:4451-4460.

110. Lengvenyte A, Strumila R, Belzeaux R, Aouizester B, Dubertret C, Haffen E, et al. (2023): Associations of white blood cell and platelet counts with specific depressive symptom dimensions in patients with bipolar disorder: Analysis of data from the FACE-BD cohort. Brain Behav Immun 108:176-187.

111. Aguglia A, Amerio A, Asaro P, Caprino M, Conigliaro C, Giacomini G, et al. (2021): High-lethality of suicide attempts associated with platelet to lymphocyte ratio and mean platelet volume in psychiatric inpatient setting. World J Biol Psychiatry 22:119-127.

112. Malone KM, Ellis SP, Currier D, John Mann J (2007): Platelet 5-HT2A receptor subresponsivity and lethality of attempted suicide in depressed in-patients. Int J Neuropsychopharmacol 10:335-343.

113. Cognasse F, Duchez AC, Audoux E, Ebermeyer T, Arthaud CA, Prier A, et al. (2022): Platelets as key factors in inflammation: Focus on CD40L/CD40. Front Immunol 13:825892.

114. Kaur S, Roberts DD (2024): Emerging functions of thrombospondin-1 in immunity. Semin Cell Dev Biol 155:22-31.

115. Nagai J, Rajbhandari AK, Gangwani MR, Hachisuka A, Coppola G, Masanidis SC, et al. (2019): Hyperactivity with disrupted attention by activation of an astrocyte synaptogenic cue. Cell 177:1280-1292.e20.

116. Yang X, Yuan C, Wang H, Wang Y, Liu M, Li Z, Zhang J (2022): Changes in serum angiogenic factors among patients with acute pain and subacute pain. Front Mol Neurosci 15:960460.

117. Lutz PE, Courtet P, Calati R (2020): The opioid system and the social brain: Implications for depression and suicide. J Neurosci Res 98:588-600.

118. Klonsky ED, May AM (2014): Differentiating suicide attempters from suicide ideators: A critical frontier for suicidology research. Suicide Life Threat Behav 44:1-5.

119. Stratman AN, Davis GE (2012): Endothelial cell-pericyte interactions stimulate basement membrane matrix assembly: Influence on vascular tube remodeling, maturation, and stabilization. Microsc Microanal 18:68-80.

120. Nation DA, Sweeney MD, Montagne A, Sagare AP, D'Orazio LM, Pacichano M, et al. (2019): Blood-brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med 25:270-276.

121. Almulla AF, Algon AAA, Maes M (2024): Adverse childhood experiences and recent negative events are associated with activated immune and growth factor pathways, the phenome of first episode major depression and suicidal behaviors. Psychiatry Res 334:115812.

122. Riad M, Mogos M, Thangathurai D, Lumb PD (2002): Steroids. Curr Opin Crit Care 8:281-284.

123. Herzog S, Galfalvy H, Keilp JG, Mann JJ, Sublette ME, Burke A, et al. (2023): Relationship of stress-reactive cortisol to suicidal intent of prior attempts in major depression. Psychiatry Res 327:115315.

124. Spaan P, Verrijp T, Michielsen PJS, Birkenhager TK, Hoogendijk WJG, Roza SJ (2025): The dexamethasone suppression test as a biomarker for suicidal behavior: A systematic review and meta-analysis. J Affect Disord 368:237-248.

125. Zieliriska KA, Van Moortel L, Opdenakker G, De Bosscher K, Van den Steen PE (2016): Endothelial response to glucocorticoids in inflam- matory diseases. Front Immunol 7:592.

126. Hage Z, Madeira MM, Koliatsis D, Tirksa SE (2024): Convergence of endothelial dysfunction, inflammation and glucocorticoid resistance in depression-related cardiovascular diseases. BMC Immunol 25:61.

127. Fan X, Yang G, Yang Z, Uhlig S, Sattler K, Bieback K, et al. (2024): Catecholamine induces endothelial dysfunction via angiotensin II and intermediate conductance calcium activated potassium channel. Biomed Pharmacother 177:116928.

128. González-Castro TB, Hernández-Díaz Y, Juárez-Rojop IE, López- Narváez ML, Tovilla-Zárate CA, Ramírez-Bello J, et al. (2018): The role of COMT gene Val108/158Met polymorphism in suicidal behavior: Systematic review and updated meta-analysis. Neuro- psychiatr Dis Treat 14:2485-2496.

129. Arango V, Ernsberger P, Sved AF, Mann JJ (1993): Quantitative autoradiography of α1- and α2-adrenergic receptors in the cerebral cortex of controls and suicide victims. Brain Res 630:271-282.
Vascular Health and Suicide

130. Galfalvy H, Currier D, Oquendo MA, Sullivan G, Huang Y-Y, John Mann JJ (2009): Lower CSF MHPG predicts short-term risk for suicide attempt. Int J Neuropsychopharmacol 12:1327-1335.

131. Ostroff RB, Giller E, Harkness L, Mason J (1985): The norepinephrine-to-epinephrine ratio in patients with a history of suicide attempts. Am J Psychiatry 142:224-227.

132. Rüesch A, Villar de Araujo T, Bankwitz A, Hörmann C, Adank A, Ip C-T, et al. (2023): A recent suicide attempt and the heartbeat: Electrophysiological findings from a trans-diagnostic cohort of patients and healthy controls. J Psychiatr Res 157:257-263.

133. Scott KM, Hwang I, Chiu W-T, Kessler RC, Sampson NA, Angermeyer M, et al. (2010): Chronic physical conditions and their association with first onset of suicidal behavior in the world mental health surveys. Psychosom Med 72:712-719.

134. Guidi J, Lucente M, Piolanti A, Roncuzzi R, Rafanelli C, Sonino N (2020): Allostatic overload in patients with essential hypertension. Psychoneuroendocrinology 113:104545.

135. Mak HW, Gordon AM, Prather AA, Epel ES, Mendes WB (2023): Acute and chronic stress associations with blood pressure: An ecological momentary assessment study on an app-based platform. Psychosom Med 85:585-595.

136. Ungvari Z, Toth P, Tarantini S, Prodan CI, Sorond F, Merkely B, Csiszar A (2021): Hypertension-induced cognitive impairment: From pathophysiology to public health. Nat Rev Nephrol 17:639-654.

137. Whitworth JA, Schyvens CG, Zhang Y, Andrews MC, Mangos GJ, Kelly JJ (2002): The nitric oxide system in glucocorticoid-induced hypertension. J Hypertens 20:1035-1043.

138. McEvoy LK, Fennema-Notestine C, Eyler LT, Franz CE, Hagler DJ, Lyons MJ, et al. (2015): Hypertension-related alterations in white matter microstructure detectable in middle age. Hypertension 66:317-323.

139. Finkelstein Y, Macdonald EM, Hollands S, Sivilotti MLA, Hutson JR, Mamdani MM, et al. (2015): Risk of suicide following deliberate self-poisoning. JAMA Psychiatry 72:570-575.

140. Das A, Huang GX, Bonkowski MS, Longchamp A, Li C, Schultz MB, et al. (2018): Impairment of an endothelial NAD⁺-H2S signaling network is a reversible cause of vascular aging. Cell 173:74-89.e20.

141. Khalil RA (2013): Estrogen, vascular estrogen receptor and hormone therapy in postmenopausal vascular disease. Biochem Pharmacol 86:1627-1642.

142. Behera C, Sikary AK, Mridha AR, Pandey RM, Satapathy S, Lalwani S, Gupta S (2019): Association of menstruation cycle with completed suicide: A hospital-based case-control study. Arch Womens Ment Health 22:771-777.

143. Parrado-Fernández C, Blennow K, Hansson M, Leoni V, Cedazo-Minguez A, Björkhem I (2018): Evidence for sex difference in the CSF/plasma albumin ratio in ~20 000 patients and 335 healthy volunteers. J Cell Mol Med 22:5151-5154.

144. Mayne SL, Moore KA, Powell-Wiley TM, Evenson KR, Block R, Kershaw KN (2018): Longitudinal associations of neighborhood crime and perceived safety with blood pressure: The multi-ethnic study of atherosclerosis (MESA). Am J Hypertens 31:1024-1032.

145. FDA-NIH Biomarker Working Group (2016): BEST (Biomarkers, EndpointS, and Other Tools) Resource. Silver Spring, MD: Food and Drug Administration Available at: http://www.ncbi.nlm.nih.gov/books/NBK326791/. Accessed May 12, 2025.

146. Goldsmith DR, Bekhbat M, Mehta ND, Felger JC (2023): Inflammation-related functional and structural dysconnectivity as a pathway to psychopathology. Biol Psychiatry 93:405-418.

147. Hunt C, Macedo E, Cordeiro T, Suchting R, de Dios C, Cuellar Leal VA, Soares JC, et al. (2020): Effect of immune activation on the kynurenine pathway and depression symptoms – A systematic review and meta-analysis. Neurosci Biobehav Rev 118:514-523.

148. Zailani H, Wang W-L, Satyanarayanan SK, Chiu W-C, Liu W-C, Sung Y-S, et al. (2024): Omega-3 polyunsaturated fatty acids and blood-brain barrier integrity in major depressive disorder: Restoring balance for neuroinflammation and neuroprotection. Yale J Biol Med 97:349-363.