bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P220: Angiotensin II Dependent And Independent Pressor Effect Of Ang-(1-12)
Authors: Forster Peter , Wysocki Jan A , Abedini Yasemin , Ye Minghao A , Ferrario Carlos M , Battle Daniel C
Published: October 2023

Background:
Ang-(1-12) serves as a functional substrate for the formation of Ang II in the blood and tissues. It remains unknown whether the hypertensive effect of Ang-(1-12) is solely caused by Ang II formation or whether the peptide itself exerts a pressor effect by binding to the AT1-receptor or a yet-to-be-identified receptor subtype. Here we examined the possibility of Ang II independent pressor effects of Ang-(1-12).

Methods:
Anesthetized male c57bl6 mice were injected with Ang II or Ang-(1-12) (0.2 μg/g BW) and the systolic blood pressure (SBP) was measured continuously for 15 minutes. To evaluate whether Ang-(1–12) vasoconstrictor activity is due to its processing into Ang II, mice were preinjected with Telmisartan or Lisinopril before Ang-(1-12) injection. We further assessed the effect of recombinant (r) ACE2 as a way to augment Ang II metabolism and therefore unravel Ang II independent pressor effects of Ang-(1-12).

Results:
Ang-(1-12) infusion led to a peak increase in SBP almost as high as Ang II (145 ±24 mmHg vs. 160±26 mmHg, respectively). The pressor effect of Ang-(1-12) was completely abolished by either Telmisartan or Lisinopril (103±11 mmHg and 98±12 mmHg, respectively). rACE2 prevented the sustained rise in SBP induced by Ang II (Fig. 1), but it did not affect the pressor effect of Ang-(1-12) (Fig. 1).

Conclusions:
Ang-(1–12) hypertensive effect is blocked by RAS blockade consistent with an action dependent on Ang II formation and coupling to AT-1 receptors. In contrast, Ang-(1–12) pressor activity is not modified when Ang II is rapidly metabolized by rACE2. These data suggest a vasoactive action of Ang-(1–12) that is, in part, independent of its conversion into Ang II.
Abstract P221: Soluble (pro)renin Receptor Contributes To 2-kidney, 1-clip-induced Renovascular Hypertension And Ischemic Nephropathy In Mice
Authors: Fu Ziwei , Zheng Huaqing , Kaewsaro Kannaree , Zou Changjiang , Yang Tianxin
Published: October 2023

The Goldblatt two-kidney, one-clip (2K1C) model features renovascular hypertension and ischemic nephropathy due to overactivated renin-angiotensin system (RAS). Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease (S1P) and implicated as a potential regulator of the RAS and renal function. Here, we examined the function and underlying mechanism of sPRR in 2K1C model by pharmacological inhibition of S1P and genetic mutagenesis of S1P cleavage site. Male 2-mo-old C57BL/6 mice were subjected to the 2K1C procedure or sham operation for 1 month, followed by a 14-day infusion of vehicle or a specific S1P inhibitor PF429242 (PF) (30 mg/kg/day via minipump). The 2K1C procedure induced a 2-fold increase in plasma sPRR, which was reduced by 50% following PF treatment. This was paralleled by improvement of renovascular hypertension (MAP:142.1±1.3 vs. 129.9±2.8mmHg, n=7, p < 0.05) and cardiac hypertrophy (HW/BW:6.3±0.3 vs. 5.0 ± 0.3mg/g, n=7, p < 0.01) accompanied with suppressed cortical and medullary renin activity, active renin content, prorenin content and total renin content in clipped kidney. Meanwhile, cortical and medullary renin mRNA level in clipped kidney was increased 3.8-fold and 5.3-fold, which was reduced by 41% and 55% respectively, following PF treatment. The level of urinary albumin, KIM-1 and NGAL was elevated 5.1-fold, 4.0-fold and 5.7-fold after 2K1C surgery, which was blunted 35%, 49% and 59%, respectively, following PF treatment. Secondly, we employed a novel mouse model with mutagenesis of the cleavage site in PRR (termed as Mutant mice) to verify the role of endogenous sPRR in 2K1C model. Similarly, the hypertensive response and ischemic nephropathy of Mutant mice to 2K1C procedure was blunted (24-day MAP: 2K1C/WT 142.5±2.1 vs. 2K1C/Mutant 128.2±3.2mmHg; 24-day urinary albumin/creatinine: 2K1C/WT 64.9±7.2 vs. 2K1C/Mutant 33.0±1.9mg/g, n=6, p < 0.05), in parallel with attenuated response of systemic and intrarenal RAS. Together, consistent results with the different approaches have established an important role of S1P-derived sPRR in regulation of the RAS and thus the pathogenesis of 2K1C-induced renovascular hypertension and ischemic nephropathy.
Abstract P225: The Reninness Score: Integrative Analysis Of Multi-omic Data To Define Renin Cell Identity.
Authors: Xue Bingjie , Medrano Silvia , Martini Alexandre G , Smith Jason , Sheffield Nathan , Gomez Roberto A , Sequeira Lopez Maria Luisa S
Published: October 2023

Renin cell
(RC)
descendants regain the endocrine renin phenotype to overcome homeostatic threats, a process known as recruitment. The determinants that control the identity, fate, and recruitment of RCs are not well understood.
We aim to 1) define the chromatin pattern that determines RC identity; and 2) develop a computational tool to score samples by similarity to that pattern.
We compared open chromatin regions (ATAC-seq) between non-renin-expressing (n = 184) and renin-expressing samples (n = 19) from three different sources and stimulation states: 1) primary RCs in basal state (WT); 2) primary RCs chronically stimulated to produce renin (recruited); and 3) constitutively renin-expressing tumoral cells. Differential analyses between the three types of RCs and the non-RCs revealed 1,525 unique open chromatin regions shared in at least two RC groups, including regions associated with RC-specific genes:
Ren1
and
Akr1b7.
Increased accessibility regions in RC groups are enriched in renin-related GO terms (
e.g.,
cAMP and Notch signaling pathway). The bZip family (
e.g.
, Atf3, p < 10
-2147
) was the most enriched motifs in tumoral cells, and MEF2 family (
e.g.
, MEF2a, p < 10
-91
) in primary cells. Co-enriched motifs

(e.g., MEIS1, p < 10
-10
; NR4A2, p < 10
-9
)

in
Ren1
and
Akr1b7
regions suggest a group of TFs govern their co-expression. In addition, we identified unique open chromatin regions and enriched motifs (
e.g.,
E2F4, p < 10
-9
; SP2, p < 10
-7
) in recruited RCs, suggesting associated TFs involved in the recruitment.Next, we used a machine-learning approach to calculate a "reninness" score by training a genomic region model with renin and non-renin ATAC-seq data. We identified a cluster of regions (n = 112,992) around the trained renin label, which included 89% (21,820 of 24,612) of the increased accessibility regions from the differential analyses. We calculated the reninness score based on the distance between the trained label embeddings and predicted samples using the trained model. Homogeneous WT RCs had the highest score, followed by renin-expressing tumoral and primary cells. Non-RCs had the lowest score. In conclusion, we identified the chromatin configurations defining the identity and recruitment of RCs and developed a computational score to quantify it.
Abstract P228: Beyond The Basics: Resistant Hypertension In A Case Of Acromegaly
Authors: Shah Hriday , Bharmal Vahid , Shingala Jay , Tummala Nayanika C , Gupta Varnika
Published: October 2023

Introduction:
Acromegaly is a rare pituitary disorder associated with hypertension. Patients with Acromegaly have a higher incidence of hypertension with age.

Case Presentation:
A 50-year-old female with resistant hypertension on 4 antihypertensives (Enalapril, Amlodipine, Metoprolol, and Chlorthalidone) for 5 years presented with Epistaxis and Blood Pressure (BP) of 210/120 mm Hg at a Tertiary care center. Intravenous Labetalol was given, reducing BP to 160/90 mmHg. The patient had fleshy lips and nose, prominent supraorbital ridges, acral enlargement, macroglossia, hyperhidrosis, and arthralgia. Investigations showed a Fasting blood sugar level of 176 mg/dL, an HbA1c level of 8.9%, a serum creatinine level of 1.0 mg/dL, an SGPT level of 42 U/L, a serum sodium/potassium level of 142/4.1 mmol/L and a triglyceride level of 274 mg/dL. Renal artery Doppler was normal, while Echocardiography revealed left ventricular hypertrophy with an ejection fraction of 55%.

Specific Investigations showed elevated Insulin-like Growth factor-1 (IGF1) levels of 604 ng/mL (normal range: 44-227 ng/mL), basal Growth Hormone (GH) 5.75 ng/mL, post-glucose GH 3.83 ng/mL, serum cortisol 8.4 μg/dL, and her prolactin levels and thyroid profile were both normal. A hypointense Sella mass measuring 0.8 cm x 1.5 cm x 1.2 cm was found on a pituitary MRI, which helped to confirm the diagnosis of Acromegaly.

The patient was managed with Octreotide, Cabergoline, and Metformin. Spironolactone 50 mg daily was added for BP control. After 15 days, BP reduced to 140/80 mm Hg. She refused transsphenoidal pituitary resection and was planned for long-acting Octreotide.

Discussion:
This case features Acromegaly associated resistant hypertension. Research suggests that hypertension in Acromegaly occurs due to excess GH/IGF-1 leading to fluid expansion, vascular resistance, and sodium retention. Spironolactone improves blood pressure, indicating a potential role for epithelial sodium channels in GH-induced sodium retention. This finding was evident in our case as well as in previous studies.

Conclusion:
This case demonstrates that acromegaly-induced Resistant hypertension can be managed with appropriate treatment, including Spironolactone.
Abstract P231: Lipoprotein Lipase Activation Is A Novel Anti-contractile Mechanism That Is Both Endothelium-dependent And Independent.
Authors: Brezner Jacob , Januario Da Costa Tiago , Wilson Emily , Araujo Fenix , Wenceslau Camilla F , McCarthy Cam
Published: October 2023

Risk factors such as hypertriglyceridemia and hypercholesterolemia are commonly attributed to the pathogenesis of atherosclerosis, however, lipoprotein metabolism is also associated with end organ damage and cardiovascular events in hypertensive patients. Lipoprotein lipase (LPL) is an important hydrolase for lipoprotein catabolism. Previous work from our lab has shown that LPL activator, NO-1886 (Ibrolipim), significantly decreased vascular contraction. Physiologically, endothelial function limits contractility and endothelial dysfunction is a hallmark of hypertension. Therefore, we hypothesized that LPL activation would cause endothelial-dependent hypocontractility. To test this hypothesis, mesenteric resistance arteries (MRA) were isolated from male Fischer 344 rats at 3 months of age (n=4-12) and mounted onto a wire myograph. Phenylephrine (PE) concentration-response curves were performed with and without LPL activator, NO-1886 (30 min). Some MRA were denuded of their endothelium or incubated with inhibitors of endothelium-dependent vasodilation. As expected, activating LPL exerted a significant anti-contractile effect in a concentration-dependent manner [KCl (%), Veh: 125±3 vs. NO-1886 (1 uM): 116.0±17 vs. NO-1886 (10 uM): 108±9* vs. NO-1886 (50 uM): 55±4* vs. NO-1886 (100 uM): 29±5*, *p<0.05 vs. Veh]. However, contrary to our hypothesis, denudation only partially restored contraction [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4* vs. NO-1886+denuded: 76±4*
#
, *p<0.05 vs. Veh,
#
p<0.05 vs. NO-1886]. This suggests that there is both an endothelium-dependent and -independent mechanism by which LPL limits contractility. Endothelial-dependent hypocontractility was found to be mediated by nitric oxide synthase [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4 vs. NO-1886+L-NAME (100 uM): 90±5*
#
, *p<0.05 vs. Veh,
#
p<0.05 vs. NO-1886]. Endothelium-independent mechanisms by which NO-1886 causes hypocontractility have yet been clarified (data not shown). Overall, this suggests that LPL has an important physiological role in controlling vascular contraction through both endothelial-dependent and -independent means and loss of LPL activity could be a novel mechanism of endothelial dysfunction in hypertension.
Abstract P232: New Anti-contractile Effect Of Skeletal Muscle Is Lost In Hypertension
Authors: Fontes Milene T , Januario Da Costa Tiago , Araújo Fênix A , Butler Landon P , Hollis Fiona , Velazquez Kandy T , Butcher Joshua T , McCarthy Cam , Wenceslau Camilla F
Published: October 2023

Since the discovery of the anti-contractile effect of perivascular adipose tissue (PVAT), it has been established that it has a crucial role in vascular function and diseases, including hypertension. However, PVAT has a minimal role in arteries surrounded by skeletal muscles (SM) compared to other vessels. During physical exercise, SM releases several factors ("myokines") that can modulate blood flow, but it is unclear if SM directly controls vascular tone in physiological conditions. The type of SM, glycolytic or oxidative, may also affect vascular dynamics. We hypothesized that SM exhibits an anti-contractile effect crucial for vascular function, which is lost in hypertension. Femoral (FA) and carotid (CA) arteries, adjacent to glycolytic and oxidative SM, respectively, from male and female SHR and Wistar (W) (12-weeks old) rats were mounted in a wire myograph in the absence (-SM) or presence (+SM) of attached or de-attached SM. Concentration-response curves (1nM-100μM) to serotonin (5-HT), phenylephrine (Phe), and thromboxane A2 analog (U46619) were performed. The presence of SM reduced contraction in FA from male (AUC 5-HT: -SM: 442±1 vs. +SM 339±2; p>0.05) and female W rats (AUC: 5-HT: -SM 258.7 ± 18.5 vs. +SM 277±21; p>0.05). Similarly, SM-induced anti-contractile effects were observed in Phe and U46619 curves and in de-attached SM. The anti-contractile effect was absent in W rats CA (AUC: 5-HT: Male: -SM 270±19 vs. +SM 257 ± 25; Female: -SM 250±35 vs. +SM 258±32). Lactate dehydrogenase inhibitor (GSK2837808A, 10nM) abolished the SM anti-contractile effect. In SHR, this anti-contractile effect in FA was not observed (AUC: 5-HT: -SM 103±27 vs. +SM 94±25). FA from SHR showed hypo-contractility to 5-HT (32%) and increased smoothelin expression, an atrophy marker, when measured by Western blot (AU: FA: W: 22861±4504 vs. SHR: 6065±1026; p>0.05). Tests of plantarflexion were performed in vivo to assess SM function. SHR showed a reduction in tetanic contraction (27%), isometric twitch force (27%), and fatigue (22%). These data reveal a new anti-contractile effect of glycolytic SM mediated by lactate and lost in hypertension. Therefore, paracrine and endocrine factors from SM represent a new frontier of vascular physiology research.
Abstract P235: The Absence Of Inhibitory G Protein Regulation By Rgs2 Increases Basal Phosphodiesterase Activity To Decrease Forskolin-stimulated Camp Generation And Enhances Myogenic Response In Uterine Arteries Of Non-pregnant Mice
Authors: Sun Bo , Dixon Alethia , Smith Nia , Osei-Owusu Patrick
Published: October 2023

G protein regulation by regulators of G protein signaling (RGS) proteins is crucial to maintaining normal vascular tone for promoting uterine vascular bed perfusion. However, the specific regulatory mechanisms involved are incompletely understood. Previously, we showed that loss of regulation of Gi/o and Gq/11 by RGS2 contributes to enhanced myogenic tone and decreased uterine blood flow in non-pregnant mice. Similarly, RGS5, closely related to RGS2, was found to fine-tune G protein signaling and modulate GPCR-evoked vascular reactivity. RGS2 and RGS5 are co-expressed in the uterine vascular bed. However, it is unclear whether their regulatory activities are coordinated in fine-tuning G protein signaling to modulate vascular tone. Here, we tested whether the combined activity of RGS2 and 5 reduces myogenic tone by negatively regulating Gi/o signaling to promote cAMP-dependent uterine artery relaxation. We used commercially available kits to measure forskolin-stimulated cAMP generation and basal phosphodiesterase (PDE) activity in freshly isolated uterine arteries from non-pregnant wild type,
Rgs5
KO and
Rgs2
KO mice. Basal tone and myogenic response to increasing intraluminal pressure were assessed using ex vivo pressure myography. We found that the absence of RGS2 but not RGS5 decreased forskolin-stimulated cAMP generation. Conversely, basal PDE activity was augmented in both
Rgs2
KO and
Rgs5
KO arteries, though the increase was less robust in
Rgs5
KO arteries. Basal tone and myogenic response were reduced in
Rgs5
KO arteries compared to WT or
Rgs2 KO
arteries in the absence or presence of nitric oxide synthase blockade with L-NAME. Activating Gi/o with dopamine increased myogenic constriction in all genotypes but less robustly in
Rgs5
KO arteries, while pre-incubation of the vessels with exogenous cAMP or PDE inhibition with IBMX normalized maximal myogenic response to similar levels in all groups. Collectively, these findings indicate that altered Gi/o regulation due to RGS2 absence enhances myogenic tone by promoting PDE-mediated inhibition of cAMP-dependent vasodilation. While both RGS2 and RGS5 negatively regulate this novel Gi/o-PDE-cAMP signaling pathway, RGS5 dampens the inhibitory efficacy of RGS2 towards Gi/o in uterine arteries.
Abstract P237: Bainiku-ekisu Attenuates Cardiac Remodeling In Angiotensin Ii-infused Mice
Authors: Torimoto Keiichi , Okuno Keisuke , Kuroda Ryohei , Reddy Vari Hymavathi , Utsunomiya Hirotoshi , Eguchi Satoru
Published: October 2023

A fruit of the
Prunus mume
is a traditional food in Japan. Recently, bainiku-ekisu, an infused juice concentrate of Japanse
Prunus mume
, is attracting attention as a health promoting supplement. Angiotensin II (AngII) plays a central role in development of hypertension. It has been reported that bainiku-ekisu treatment attenuates the growth-promoting signaling induced by AngII in vascular smooth muscle cells. However, whether bainiku-ekisu has any effect on an animal model of hypertension remains unknown. Therefore, this study was designed to explore the potential anti-hypertensive benefit of bainiku-ekisu utilizing a mouse model of hypertension with AngII infusion. 8- to 10-week-old male C57BL6 mice were randomly divided into four groups and infused with Ang II (1 μg/kg/min) for 2 weeks via osmotic mini-pump or sham-operated, and given 1% BE containing water (BEW) or normal water (control) for 2 weeks. Blood pressure was evaluated every other day by tail cuff measurement and at 2 weeks by telemetry. Cardiac hypertrophy was assessed by heart-to-body weight ratio. After 2 weeks, mice were euthanized, and the aorta and heart collected. Extracted aortas and hearts were fixed and used for histological studies to evaluate vascular remodeling. Increase in heart-to-body weight ratios by Ang II were unaltered by BEW. Aortic medial hypertrophy was observed in control mice (n=5) after 2 weeks of Ang II infusion, which was attenuated in BEW group (96 μm vs. 71 μm, respectively, p<0.01). Control mice with angiotensin II infusion showed cardiac matrix deposition, which was attenuated in BEW group. In addition, attenuation of hypertension was observed in Ang II-infused mice with BEW treatment. We also observed attenuation of protein synthesis induced by AngII with BE incubation in cultured aortic VSMC. In conclusion, BEW prevented Ang II-induced vascular remodeling and hypertension. Potential cardiovascular health benefit to taking BE as a functional food should be further studied.
Abstract P303: Contribution Of Adrenal Leptin Receptor To The Control Of Aldosterone Synthase Expression And Endothelial Function In Female Mice
Authors: Ono Yoichi , Antonova Galina , Kennard Simone , Breault David , Belin De Chantemele Eric J
Published: October 2023

While premenopausal women are severally affected by the current obesity epidemic, the mechanisms whereby obesity promotes vascular dysfunction in this population remain ill-defined. We previously demonstrated that the adipokine leptin acts on the adrenal gland to promote aldosterone production and that leptin-mediated aldosterone production impairs endothelial function in female mice only. Herein, we investigated whether these mechanisms are dependent on the presence of leptin receptors (lepR) in adrenal glands. We generated lean female mice exhibiting a selective deficiency in LepR in adrenals (AdKO), and obese mice expressing LepR in adrenal glands (db/ad
+
) only. Under baseline conditions, AdKO exhibited no alteration in adrenal CYP11B2, renal renin level, aortic endothelial function (measured by acetylcholine-mediated relaxation), arterial stiffness (pulse wave velocity test, PWV), or metabolic parameters including heart and visceral adipose tissue (VAT) weights, fluid amount, glycemia, and HbA1c. Chronic leptin infusion for a week induced trends towards increases in adrenal CYP11B2 (ΔΔCt 1.10±0.12 vs 2.01±0.51, P=0.077), aldosterone (557±95 vs 918±526 pg/ml, P=0.859), and renin levels in WT. AdKO conferred no protection against any of these changes. Leptin infusion impaired endothelial function in WT (Emax 73.3±3.9 vs 52.8±3.1%, P=0.019), which was exacerbated in AdKO (52.8±3.1 vs 34.3±4.1%, P=0.052). However, leptin infusion did not change PWV in WT (3.93±0.22 vs 4.17±0.32 m/s, P=0.999), but induced a trend towards a decrease in AdKO (4.17±0.32 vs 3.11±0.44 m/s, P=0.228). Restoration of adrenal LepR in db/db mice did not alter CYP11B2 nor aldosterone levels but increased renin (ΔΔCt 1.04±0.11 vs 1.48±0.12, P=0.029), heart weight, VAT weight (5.14±0.29 vs 6.52±0.62 g/g, P=0.052), and HbA1c (5.7±0.2 vs 6.9±0.4 %, P=0.035). Although PWV was worsened in db/ad
+
(5.40±0.27 vs 6.39±0.49 m/s, P=0.035), db/ad
+
presented improved relaxation compared to db/db (58.5±5.6 vs 73.0±2.2%, P=0.067), inconsistent with our hypothesis. Collectively these data indicate that adrenal LepR might not directly control adrenal CYP11B2 levels expression but latently contributes to changes in endothelial function and arterial stiffness.
Abstract P306: Beta-arrestin Biased Signaling Is Not Necessary For The Hypotensive Actions Of 5-HT
7
Receptor Stimulation: Use Of Serodolin
Authors: Watts Stephanie W , Garver Hannah , Morisset-Lopez Severine , Fink Gregory D
Published: October 2023

The 5-hydroxytryptamine 7 receptor (5-HT7) is necessary for 5-HT to cause a concentration-dependent vascular relaxation and hypotension. 5-HT
7
is recognized as having biased signaling, transduced through either Gs or β-arrestin. It is unknown whether 5-HT
7
signals in a biased manner to cause relaxation/hypotension. This is important to know to maximize therapeutic effects of 5-HT
7
receptor stimulation. Here, we used the recently described β-arrestin selective 5-HT
7
receptor agonist serodolin to test the hypothesis that 5-HT
7
activation does not cause vascular relaxation or hypotension via the β-arrestin. Abdominal aorta (no functional 5-HT
7
) and vena cava (functional 5-HT
7
) from male Sprague Dawley rats were used in isometric contractility studies. Serodolin (1 nM - 10 uM) did not change baseline tone of either vessel when compared to vehicle control, and was unable to relax the endothelin-1 (ET-1) contracted vena cava or aorta. In the aorta, serodolin acted as a 5-HT
2A
receptor antagonist, evidenced by a rightward shift in 5-HT-induced concentration response curve (pEC
50
5-HT [M]: Veh = 5.2±0.15; 100 nM Ser = 4.49±0.08). In the vena cava, serodolin acted as a 5-HT
7
receptor antagonist, by 1) shifting concentration response curve to 5-HT left and upward [% 10 uM NE contraction; Veh = 3.2±1.7; Ser (10 nM) = 58±11%; p< 0.05] and blocking relaxation of the contracted tissue to the 5-HT
1A/7
agonist 5-carboxamidotryptamine. Studies were conducted
in vivo
in normotensive male rats under isoflurane anesthesia. 5-HT or serodolin were infused at 5, 25 and 75 ug/kg/min, iv). 5-HT caused concentration-dependent depressor responses at the two lowest infusion rates (5-HT
7
-mediated), and pressor responses at the highest infusion rate (5-HT
2A-
mediated). Serodolin caused only small depressor responses at all three infusion rates. In another group of animals serodolin was given at a dose of 1 ug/kg, sc. Over one hour, basal blood pressure was unaffected; subsequent infusion of 5-HT caused minimal changes in blood pressure. Collectively the data indicate that serodolin functions as a 5-HT
7
antagonist with additional 5-HT
2A
blocking properties and that 5-HT
7
activation does not cause vascular relaxation or hypotension via the β-arrestin pathway.
Abstract P309: Descending Thoracic Aorta Perivascular Adipocytes Adipogenesis Is Defined By Their Anatomical Location
Authors: Contreras G. Andres , Rendon Cristian J , Watts Stephanie W
Published: October 2023

Hypertension, atherosclerosis, and aneurysms alter thoracic aorta structure. Aortic lesions in these diseases show unique anatomical distribution. Calcifications and atherosclerotic lesions occur more frequently in the posterior wall of the aorta compared to other regions. Descending thoracic aorta's perivascular adipose tissue (PVAT) is distributed in 3 strips: one is located anterior to the aorta (
AP
), and two positioned laterally to the posterior wall of the vessel and adjacent to thoracic vertebrae (
LP
). Evidence indicates PVAT LP’s adipocytes derive from different progenitors than those from AP. The implications of this ontology and aortic PVAT distribution on the development of its adipocytes and other cellular components is unknown. We hypothesize that progenitor’s anatomical location influences their adipogenic potential. LP and AP were collected from male SD rats (n=7) at 10 wks of age to harvest progenitors by outgrowth expansion. Progenitors were differentiated for 4 d in adipogenic media. Adipogenesis was evaluated by lipid droplet and triglyceride quantification using Live-Cell
®
imaging. RNA from progenitors and adipocytes was sequenced in Illumina NextSeqData, and Differential Expressed Genes identified. Enrichment and network analyses were performed in Ingenuity Pathways (IPA). Ontogeny gene markers
Myf5
and
Sm22a
had higher expression in LP than AP. LP progenitors had 213% higher adipogenesis rate than AP (P<0.05). This change was accompanied by increased transcription of adipogenesis regulator
Cepba
and the intracellular FA transporter
Fabp4
and lower expression of the lipase ATGL (
Pnpla2
) and the membrane channel supporting FA export FATP6 (
Slc27a6
) in LP vs. AP. IPA analysis showed upregulation of antiadipogenic pathways adrenomedullin and endothelin in AP. Anatomical site influenced the extracellular marker gene profile with LP having a higher transcription of collagens 1a1, 6a1, and elastin vs. AP. Taken together, our findings provide evidence supporting differences in adipogenic activity and extracellular matrix secretion between aorta’s LP and AP PVAT. These differences may support anatomical location as a predisposing factor for aortic lesions associated with hypertension, atherosclerosis, and aneurysms.
Abstract P311: The Association Of Locomotive Syndrome/low Bone Mineral Density And Increased Arterial Stiffness
Authors: Matsumoto Chisa , Tomiyama Hirofumi , Nakano Hiroki , Matsuura Mari , Shiina Kazuki , Yamashina Akira
Published: October 2023

Background:
Both frailty and osteoporosis have been regarded as risk factors of cardiovascular disease (CVD). However, it has not been reported whether the combination of osteoporosis and frailty is associated with arterial stiffness, a marker for CVD. The objective of this study is to evaluate the association of and arterial stiffness.

Hypothesis:
We hypothesized combination of frailty and osteoporosis is associated with increased arterial stiffness.

Methods:
Japanese Subjects above 50 years old who underwent annual health-checkup were enrolled in this cross-sectional study. Subjects with history of CVD and dementia were excluded. Arterial stiffness was evaluated by brachial-ankle pulse wave velocity (baPWV). Forearm bone mineral density (BMD) was measured by dual energy X-ray absorptiometry and young adult mean (YAM) less than 80% was defined as low bone mineral density (LB). We evaluated frailty by screening Locomotive syndrome (LS) assessed by the questionnaires (GLFS-25) and physical performance tests consisted of those for a two-step test and a stand-up test according to the guidance of the Japanese Orthopedic Association. The association of combination of LS and LB, LS, LB and baPWV was assessed by multivariable linear regression analysis adjusted for conventional CVD risk factors.

Results:
Among 137 subjects (mean age: 59±6 years), 7 subjects (20%) had both LS and LB. The numbers of subjects who had only LS, only LB, and none of those were, 58, 10, 62, respectively. BaPWV in subjects with combination of LS and LB was highest compared to subjects with only sarcopenia, only obesity, and none of those (Figure, p=0.01). Multivariable linear regression analysis revealed that the combination of LS and LB, LS, LB, were gradually associated with increased arterial stiffness even after adjustment for conventional CVD risk factors. (β=57±21, p<0.01).

Conclusion:
The combination of LA and LB was significantly associated with increased arterial stiffness. Further research on frailty/osteoporosis and arterial stiffness is warranted.
Abstract P312: Three-Month Human Endothelin-1 Endothelial Overexpression Up-Regulated
Khdrbs3
And Caused
Vegfa
And
Nrp2
Alternative Splicing In Mesenteric Arteries Of Male Mice
Authors: Paradis Pierre , Berillo Olga , Coelho Suellen C , Ferreira Nathanne d , Richer Chantal , sinnett daniel , Schiffrin Ernesto L
Published: October 2023

Background:
Transgenic mice with tamoxifen-inducible endothelium-restricted human endothelin-1 overexpression (ieET-1) exhibited blood pressure (BP) elevation 3 weeks or 3 months after induction, and vascular injury was observed after 3 months. We hypothesized that 3-week or 3-month exposure to ET-1 overexpression leads to gene dysregulation in mesenteric arteries (MAs).

Methods:
Ten to 12-week old male ieET-1 mice and control ieCre mice expressing a tamoxifen-inducible Cre recombinase under the control of the endothelium-specific
Tie2
promoter were treated with tamoxifen (1 mg/kg/day, s.c.) for 5 days and euthanized 16 days or 3 months later. RNA was extracted from MAs and used for total RNA-sequencing using Illumina HiSeq-2500. Differentially expressed (DE) genes were identified with fold change >1.3 and
P
<0.005. DE genes were validated by reverse transcription-quantitative PCR (RT-qPCR) using another set of mice. Alternative splicing was revealed by Spladder and validated by RT-qPCR in MAs.

Results:
RNA-sequencing revealed DE genes after 3-week (54) and 3-month ET-1 overexpression (7). Alternative splicing changes in mRNAs were revealed after 3-week (39) and 3-month ET-1 overexpression (21). One of the 3 genes validated by RT-qPCR,
Khdrbs3,
encodes KH domain containing RNA binding signal transduction associated 3 that regulates exon retention of some mRNAs including exon 7 of vascular endothelial growth factor A (
Vegfa
).
Khdrbs3
was up-regulated after 3-week (fold change: 2.4±0.1 vs 1.0±0.1,
P
<0.05) and 3-month ET-1 overexpression (2.3±0.3 vs 1.3±0.1,
P
<0.05).
Vegfa
exon 7 retention was validated by demonstration of up-regulation of

Vegfa
164

(1.3±0.1 vs 0.9±0.1, P<0.05) and

Vegfa
188

isoforms (1.1±0.1 vs 0.9±0.1, P<0.05) after 3-month ET-1 overexpression (
P
<0.05). Neuropilin 2 (
Nrp2
) that interacts with VEGFA receptors was one of DE genes with alternative splicing in exon 17 (

Nrp2
a

isoforms). Predicted

Nrp2
a

down-regulation (
P
<0.05) was validated by RT-qPCR showing a decrease after 3-month ET overexpression (0.6±0.1 vs 1.1±0.2,
P
<0.05).

Conclusions:
This study demonstrated that 3-month ET-1 overexpression up-regulated
Khdrbs3
and alternative splicing of
Vegfa
and
Nrp2
, which may play a role in vascular injury in hypertension.
Abstract P313: Chronic Circadian Disruption Impairs Blood Pressure Rhythm And Leads To Vascular Disease In Mice
Authors: Pati Paramita , Colson Jackson , Dunaway Luke S , Rhoads Megan K , Pollock David M , Pollock Jennifer S
Published: October 2023

Shift workers have an elevated risk of developing hypertension and higher incidence of cardiovascular disease. Circadian rhythm disruption increases cardiometabolic disease risk in both humans and animals. We hypothesized that chronic circadian disruption (CCD) impairs cardiovascular rhythms and leads to vascular disease. Male 8-week old C57BL/6J mice were subjected to a standard light/dark cycle (12-h light, 12-h dark, control) or a CCD protocol (10-h light, 10-h dark, T20) with
ad libitum
food and water for 10 wks. T20 mice had an increased rate of weight gain (n=6, p=0.04; time: p<0.001, light cycle: p<0.001). Mean arterial pressure (MAP), heart rate (HR), and activity were measured by telemetry after 10 weeks of CCD. Control mice (12:12 LD) had significant diurnal variation in MAP, while T20 mice (10:10 LD) lacked diurnal variation (control 119±3 vs.101±2 mm Hg, dark vs. light, p<0.001; T20 114±13 vs.113±12 mm Hg, dark vs. light, p=0.86; n=3-4). Control mice had a diurnal variation in HR which was absent in T20 mice (Control 584±11 vs. 511±4 bpm, dark vs. light, p=0.001; T20- 537±14 vs. 526±5 bpm, dark vs. light, p=0.48; n=3-4). Dark phase HR was significantly lower in T20 mice (p=0.01, control vs. T20). Control mice had a light-dark difference in activity, while T20 mice lacked diurnal variation in activity with significantly higher light phase activity (p=0.04, control vs. T20). Aortic pulse wave velocity (PWV), a measure of vascular stiffness, was significantly higher after 6 weeks in T20 mice compared to control mice (Control: 1.60±0.1 m/s; T20: 2.25±0.1 m/s; n=6, p=0.0037), although aortic wall thickness was similar between groups. Wire myography in isolated aortic rings was used to assess vascular reactivity with cumulative concentration responses to phenylephrine (PE) and acetylcholine (ACh). CCD reduced sensitivity (EC50) to PE-induced vasoconstriction (Control: -6.92±0.06 M; T20: -6.74±0.04 M, n=6, p=0.03), while there were no significant changes seen in the ACh sensitivity or maximal response. These data show that CCD impairs cardiovascular and behavioral rhythms linked to the development of aortic stiffness.
Abstract P315: Angiotensin Ii Type 1a Receptor Expressed In Smooth Muscle Cells Is Required For Vascular Remodeling In Mice Infused With Angiotensin II
Authors: Torimoto Keiichi , Reddy Vari Hymavathi , Okuno Keisuke , Cicalese Stephanie M , Eguchi Satoru
Published: October 2023

Angiotensin II (AngII) type 1A (AT
1A
) receptors play a critical role in hypertension and cardiovascular remodeling in mice infused with AngII. Although vascular remodeling, a significant contributor to organ damage, occurs concurrently with hypertension in AngII infused mice, the contribution of smooth muscle AT
1A
in this process remains unexplored. Accordingly, it is hypothesized that smooth muscle AT
1A
receptors exclusively contribute to both medial thickening and adventitial fibrosis regardless of the presence of hypertension. 1 μg/kg/min AngII was infused for 2 weeks in two distinct AT
1A
receptor silenced mice, knock-in
Tagln
-mediated constitutive smooth muscle AT
1A
receptor silenced mice and
Myh11
-mediated inducible smooth muscle AT
1A
silenced mice for evaluation of hypertensive cardiovascular remodeling. Medial thickness, adventitial collagen deposition and immune cell infiltration in aorta were increased in control mice but not in both smooth muscle AT
1A
receptor silenced mice. Coronary arterial perivascular fibrosis in response to AngII infusion was also attenuated in both AT
1A
receptor silenced mice. AngII-induced cardiac hypertrophy was attenuated in constitutive smooth muscle AT
1A
receptor silenced mice. However, AngII-induced cardiac hypertrophy and hypertension were not altered in inducible smooth muscle AT
1A
receptor silenced mice (SBP control 148 vs knockout 149 mmHg). In conclusion, smooth muscle AT
1A
receptors mediate AngII-induced vascular remodeling including medial hypertrophy and inflammatory perivascular fibrosis regardless of the presence of hypertension. Our data suggest an independent etiology of blood pressure elevation and hypertensive vascular remodeling in response to AngII.
Abstract P326: Engaging Patients In Home Blood Pressure Monitoring
Authors: Green Beverly B , Haas Phil , Hansell Laurel , Hsu Clarissa W , Jone Tae , Luce Casey , Munson Sean , Ralston James
Published: October 2023

The COVID-19 pandemic resulted in fewer clinic-based blood pressure (BP) measurements and worsening hypertension control, but new opportunities for taking hypertension care out of the office and into patients homes using self-measured BP (SMBP).

Methods:
We performed a mixed methods study of 6489 patients at Kaiser Permanente Washington with hypertension had high BP (
>
140/90 mmHg) at their last clinic encounter and had received a secure email message requesting a follow-up BP, either by sending in a home BP measurement by secure email or coming into clinic for a kiosk or medical assistant BP measurement. Quantitative assessments included the percent and characteristics of patients: 1) with BPs in the EMR at 3 months versus no BP; 2) clinic BPs versus home BPs; and 3) controlled vs uncontrolled BP (HEDIS definition). We conducted semi-structured phone interviews with 22 participants from the quantitative cohort, oversampling from those who sent in home BPs and identified key themes and made recommendations to the delivery system for engaging patients in home BP monitoring.

Results:
Of the 6489 individuals, 53.8% had a BP in the EMR in the 3 months after the outreach attempt, Individuals with a BP were more likely to be older (age 65+, 64.9%), women (58.3%), and white race (58.0%). Individuals with no BP in the EMR were more likely to be less than age 50 and Asian Of the patients with a BP in the EMR by 3 months and a primary care or email encounter, 81.1% (2021) had a clinic BP and 18.9% (467) had a home BP. People identified as White race were most likely to have a home BP, whereas people identified as Black race were least likely (20.5% vs. 9.5%). Home BPs were significantly more likely to be <140/90 mmHg as compared to clinic BPs (75.6% versus 52.4%, P<0.001). Important themes from interviews included variation in patient understanding of high BP and BP targets, questions about selection of BP monitors and measurement schedules, preferences for telehealth and follow-up communications, and needs for educational support.

Discussion:
Most follow-up BPs were clinic-based. Quantitative assessment revealed disparities in uptake of home BP measurement. Qualitative assessments provided insights for program design and increasing patient engagement in SMBP.
Abstract P327: “The More Data, The Better”: Patient Experiences With Blood Pressure Measurement For Hypertension Diagnosis
Authors: Hansell Laurel , Hsu Clarissa , Munson Sean , Margolis Karen L , Thompson Matthew , Hall Yoshio , Anderson Melissa , Ehrlich Kelly , McClure Jennifer , Green Beverly B
Published: October 2023

Background:
Out-of-office blood pressure (BP) measurement is recommended when making new hypertension diagnoses. However, in current practice, hypertension is primarily diagnosed using clinic BP measurements.

Objective:
To understand patient attitudes about the accuracy and patient-centeredness of different BP measurement and hypertension diagnostic methods.

Design:
Qualitative study within a randomized controlled diagnostic study comparing the accuracy and acceptability of clinic BP, home BP monitoring (HBPM), and kiosk BP (in a waiting room or pharmacy) for diagnosing hypertension among patients in an integrated delivery system. All participants also completed 24-hour ambulatory blood pressure monitoring regimen (ABPM).

Participants:
Qualitative interview participants (aged 31-76 years) were recruited from the main study with a goal of balancing by study arms, measurement result (high vs normal ABPM), hypertension diagnosis status at 6 months, gender, and age.

Approach:
We conducted semi-structured interviews at two time points—shortly after completion of diagnostic testing and 6 months later—to explore attitudes and behaviors related to the different BP measurement diagnostic methods.

Key results:
Interview participants (n=35) found HBPM to be comfortable, convenient, and low burden, and believed it produced accurate results. Participants reported higher confidence in high BP measurements from HBPM or ABPM compared to measurement in clinics. Clinic measurements were reported as less convenient than HBPM. Participants overall did not favor kiosks due to concerns about accuracy and privacy. ABPM was described by participants as the most accurate method, partly due to repeated measurements over the 24-hour period in real-world contexts, but many found it uncomfortable and disruptive. Participants also noted that methods that involved repeated measures such as HBPM and ABPM were especially influential in making their own personal decision as to whether or not they had hypertension.

Conclusions:
Our findings suggest that strategies to enhance HBPM implementation for hypertension diagnosis in primary care may improve diagnosis and patient understanding of hypertension.
Abstract P330: Two Rodent Models Of Augmented 24-hour Blood Pressure Variability Showing Similar Pathophysiological Features: Rats Infused With Norepinephrine Or Angiotensin II
Authors: Kato Johji , Matsuzaki Minami , Jiang Danfeng
Published: October 2023

Background:
Augmented fluctuation of blood pressure (BP), so-called BP variability (BPV), was shown to be associated with cardiovascular diseases independently of BP levels. Recently we reported that 24-h BP variability is augmented in rats continuously infused with norepinephrine (NE) or angiotensin II (Ang II), assuming these animals as models of augmented BPV seen in ambulatory BP monitoring (ABPM) of humans. This study was aimed to clarify the underlying mechanisms for augmented BPV and the effects of azelnidipine, a calcium channel blocker, in rats infused with Ang II or NE.

Methods and Materials:
Nine-week-old male Wistar rats were continuously infused with subcutaneous 30 μg/h NE or 5.2 μg/h Ang II with or without oral administration with 30 mg/kg/day azelnidipine (Azl) for 14 days (n=8 to 9 per group). BPV was evaluated before and after 14 days of the infusions, using standard deviations (SDs) of systolic and diastolic BP (SBP and DBP) recorded every 15 min under an unrestrained condition by a radiotelemetry system. Baroreceptor reflex sensitivity (BRS) was quantified with a sequence analysis, while sections of the aortic arch, where baroreceptors are thought to be located, were microscopically evaluated by computerized measurement.

Results:
Both SBP and DBP rose following infusion of NE or Ang II, while these increases were attenuated by Azl (P<0.01). SDs of SBP at the light (L) and dark (D) cycles were increased by NE (L, +94%; D, +117%, P<0.01) and Ang II (L, +94%; D +95%, P<0.01), with similar changes in SDs of DBP. These increases in SDs were attenuated following treatment with Azl almost to the control level (P<0.01). Augmented BPVs in both the NE and Ang II groups were accompanied by reductions in BRS (P<0.05) and by thickened medial area of the aortic arch (P<.0.01), while Azl alleviated impairment of BRS and aortic medial thickening (P<0.05). When analyzed for all groups by a simple regression, augmented BPV correlated with impairment of BRS (r=-0.54, P<0.01), which was associated with aortic medial area (r=-0.56, P<0.01).

Conclusion:
Rats infused chronically with NE or Ang II are models of increased 24-h BPV, both of which similarly showed impaired BRS and thickening medial layer of the aortic arch in association with augmented BPV.
Abstract P333: Self-measured Blood Pressure Monitoring During The Covid-19 Pandemic Among Persons Living In Rural Areas
Authors: Vaughan Adam S , Fang Jing , Wall Hilary , Coronado Fatima
Published: October 2023

Self-measured blood pressure monitoring (SMBP) plus clinical support can help control blood pressure among people with hypertension. The COVID-19 pandemic drove increased telehealth use, presenting an opportunity for increased SMBP use among groups with limited healthcare access. This study examined changes in the use and electronic reporting of SMBP among US adults aged ≥18 years with hypertension living in rural areas by race and ethnicity. With data from the Behavioral Risk Factor Surveillance System in 2019 and 2021, we used weighted Poisson regression to estimate the annual prevalence of adults with hypertension who reported using SMBP and who reported sharing SMBP results by phone or Internet. For each race and ethnicity and outcome, we estimated adjusted prevalence ratios (aPR) comparing 2021 to 2019, adjusted for age group, income, insurance status, sex, and education. The prevalence of SMBP use did not significantly change for any race or ethnicity from 2019 to 2021 (Figure). White, Black, and Hispanic adults reported SMBP measurements electronically more in 2021 than 2019 (aPR [95% CI]: 1.5 [1.1-1.9], 2.7 [1.2-6.0], 3.9 [1.7-9.0], respectively). Prevalence of electronic reporting among adults living in rural areas remained low in 2021, ranging from 10.5% in adults of other races to 21.7% in Hispanic adults. Despite changes that helped SMBP implementation during the COVID-19 pandemic, SMBP use did not change; electronic reporting increased but remained rare. Because SMBP can make blood pressure control more convenient and accessible, additional policies and programs can facilitate SMBP implementation, especially among populations with limited healthcare access.
Abstract P334: Comparing A Cuffless Device With Traditional Home Blood Pressure Monitoring In A Remote Hypertension Management Program: Primary Results Of The COOL-BP Study
Authors: Fisher Naomi D , Lee Simin , Unlu Ozan , Perruchoud David , Sola Josep , Shah Jay , Chin Nicholas , Figueroa Christian , Collins Emma , Ruggierorru Ryan , Gabovitch Dan , Zelle David , Cannon Christopher P , Scirica Benjamin
Published: October 2023

Background:
Innovative BP measurement technology with cuffless devices has the potential to enhance HTN control, especially with remote HTN management.

Methods:
Patients with uncontrolled BP at Mass General Brigham were managed by navigators and pharmacists in a digital remote HTN management program, based on home BP monitoring (HBPM) with digitally-connected arm cuffs. A subset was enrolled into the 6-month COntinual vs OccasionaL (COOL-BP) study, testing a wrist cuffless device (Aktiia SA, Switzerland). Asynchronous daytime weekly BP averages from both modalities were compared, including all readings from the cuffless device, and guideline-directed twice daily readings from HBPM. Of 38 patients who measured their BP with both devices, 25 collected at least one overlapping week of BPs with each device, with a minimum of 12 valid daytime readings over at least 3 days per week.

Results:
The scatter plots (Figure, top) showed moderate to strong correlation between 72 weekly average daytime BPs by HBPM and the cuffless device (r=0.57 for SBP; r=0.64 for DBP). The difference plots (Figure, bottom) showed that cuffless SBP was higher than HBPM (4.9±11.3 mmHg, p=0.01), while DBP was lower (-4.2±7.2 mmHg; p=0.003). Importantly, cuffless BPs were non-simultaneous with HBPM, included measurements in different body positions, and were much more numerous, which could help explain the differences between BP averages.

Conclusion:
Daytime weekly average home BPs with continual monitoring using a cuffless wrist device were comparable to those measured by traditional HBPM. These findings encourage exploring the use of continual cuffless monitoring for the remote management of HTN.