bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Estrogen and Hormonal Birth Control on Vascular Function in Premenopausal Women with Type 1 Diabetes
Authors: Simon Abigayle B. , Derella Cassandra C. , Blackburn Marsha , Thomas Jeffrey , Layman Lawrence C. , Harris Ryan A. 
Published: May 2022

BACKGROUNDCirculating concentrations of estrogen throughout the menstrual cycle contribute to the cyclic increase in vascular function in healthy women. Evidence in animals; however, has identified a vasoconstrictive role of estrogen in the presence of diabetes. The present investigation sought to determine the role of estrogen throughout the menstrual cycle on vascular function and the impact of hormonal birth control (HBC) on vascular function in premenopausal women with type 1 diabetes (T1D).METHODS33 women with T1D (HbA1c=8.5±1.7%, age=26±8 years, BMI=27.1±5.6 kg/m2) and 20 healthy women (HbA1c=5.2±0.3%, age=25±7 years, BMI=23.9±3.8 kg/m2) participated in this study. A subgroup of 9 women with T1D taking oral HBC (HbA1c=8.3±2.1%, age=25±7 years, BMI=29.0±6.4 kg/m2) and 9 demographically matched women with T1D not taking HBC (HbA1c=8.3±2.1%, age=23±6 years, BMI=25.7±5.0 kg/m2), was then analyzed. In all participants, a venous blood sample was collected to determine circulating concentrations of estrogen. Flow‐mediated dilation (FMD), the gold standard for measuring endothelial function non‐invasively, was performed during menses and the late follicular phase of the menstrual cycle to represent periods of low and high estrogen, respectively. Menses was confirmed by a positive hemolytic urological multistix test, and the late follicular day was determined using an ovulation predictor kit for those not on HBC. For those on HBC, baseline was conducted during their placebo week, and the “late follicular” day was conducted during the second week of the HBC pills.RESULTSA similar increase was observed in estrogen from menses to late follicular in both the T1D and control group. (Δ estradiol: T1D=74.5±85.4 pg/mL, controls= 88.2±79.1 pg/mL, p=0.561). A significant interaction (p=0.044) was observed between FMD across the menstrual cycle. Specifically, FMD was significantly greater (p=0.043) during late follicular phase in controls compared to T1D, albeit having a similar (p=0.666) FMD during menses. Within the subgroup analysis, there was no interaction between FMD and menstrual cycle between both T1D groups (p=0.555); however, there was a significant (p=0.04) menstrual cycle phase main effect indicating that vascular function overall was greater in women with T1D on HBC compared to women with T1D not on HBC.CONCLUSIONThese data suggest that estrogen decreases vascular function in the presence of diabetes. In addition, HBC may reduce cardiovascular disease risk in premenopausal women with T1D.
Chemotherapy, Microvascular Function, and Angiogenesis ‐ a Longitudinal Study
Authors: Norwood Toro Laura E. , Hader Shelby N. , Terwoord Janee D. , Didier Daniela , Kong Amanda , Beyer Andreas M. 
Published: May 2022

RationaleAnti‐cancer therapies (CTx), such as anthracyclines (e.g., doxorubicin, Dox), have known anti‐angiogenic effects in vitro, and inhibition of angiogenesis has known cardiotoxic effects. Cardiovascular (CV) toxicities that result from CTx significantly contribute to the morbidity and mortality of breast cancer survivors. While the negative impact of CTx, including Dox, on isolated cardiomyocytes is well‐established, significantly less is known about the effects of CTx on microvascular (MV) function and angiogenic potential in patients. Our goal was to understand how CTx damages the microcirculation in order to further the understanding of mechanisms that contribute to systemic cardiovascular toxicity. Utilizing a longitudinal study design of neoadjuvant breast cancer patients, adipose tissue was collected before, during, and after CTx treatment.MethodsAngiogenic potential was evaluated using a matrigel angiogenesis assay of patient adipose. Data are presented as a percentage of wells with capillary sprouts and area of capillary sprouting ± standard error. In addition, we investigated the expression of a subset of genes involved in angiogenesis regulation (initiation/sprouting, migration, ECM remodeling, maturation, and permeability). Freshly isolated microvessels were evaluated for dilation to flow (FMD) and acetylcholine (Ach). Cardiac function was monitored via standard clinical echocardiogram. Significance was determined using paired t‐test (p ≤ 0.05*).ResultsPercentage of wells with capillary sprouts was impaired in adipose samples collected during CTx (26.3% ± 13.6%, N=4) and one month post CTx (44.3% ± 9.1%*, N=9) compared to pre‐CTx (67.1% ± 4.7%*, N=13). However, sprouting area only changed during CTx (15.0 mm2± 8.5*, N=4) compared to pre‐CTx (68.3 mm2± 10.2, N=13). One month post CTx, the sprouting area (56.8 mm2± 19.1, N=9) was not significantly different than pre‐CTx. Supporting this change in angiogenesis function, we observe changes in expression of genes involved in initiation of angiogenesis during CTx (VEGFA, VEGFB, FLT1) that show recovery of expression post‐CTx. We also observe changes in expression of genes involved in maturation of angiogenesis post CTx (KLF4, VCAM1, MMP8). Some clinical signs of reduced cardiac function were observed post CTx after microvascular and angiogenic changes were observed.ConclusionOur data show pathological impairment in angiogenic potential and gene expression in adipose tissue of breast cancer patients in a longitudinal study. These data support our observed defects in MV function (response to FMD and Ach) during and after CTx treatment. We observed significant reductions in MV function and capillary sprouting during treatment with CTx in the absence of a clinically relevant reduction in cardiac function. Our findings suggest that CTx‐induced MV dysfunction precedes and may contribute to future adverse CV events.
Leg microvascular function remain robust throughout the female menstrual cycle
Authors: Georgescu Vincent , Jarrett Catherine , Thurston Taylor , Weavil Josh , Amann Markus 
Published: May 2022

BACKGROUNDThe female menstrual cycle (MC) is characterized by fluctuating concentrations of estrogen and progesterone. While the impact of these vasoactive sex hormones on macrovascular function has received considerable attention, little is known about their influence on the microvasculature. Since the microvasculature ultimately determines skeletal muscle perfusion, a thorough understanding of the influence sex hormones have on microvascular function is needed. It was therefore the purpose of this study to investigate microvascular function, as assessed via the passive leg movement technique (PLM), of eumenorrheic females at three unique gonadal hormone profiles.METHODSSix healthy females (age: 22 ± 2 years; height: 168 ± 2 cm; weight: 59 ± 2 kg) were studied during the early follicular (EF; days 1‐4), late follicular (LF; days 8‐12), and mid luteal (ML; days 8‐10 post luteinizing hormone peak) phases of their MC. Venous blood was collected and analyzed for estrogen and progesterone concentrations. For each visit, subjects arrived at the laboratory in a fasted, rested state and at the same time of day. Passive leg movement (1 Hz for one minute; 90‐degree range of motion at the knee) was performed in a seated position. At rest and during PLM, leg blood flow (femoral artery; QL) was measured with Doppler ultrasound, while heart rate (HR), cardiac output (CO), and mean arterial pressure (MAP) were continuously measured via Finapress.RESULTSAll females presented traditional patterns of hormonal variation throughout the MC. Estrogen (EF: 144 pg/mL, LF: 239 pg/mL, ML: 359 pg/mL) was different at each phase (p < 0.05), while progesterone was similar during EF and ML (~0.2 ng/mL; p = 0.2), but significantly higher during ML (~6.8 ng/mL, p = 0.02). The area under the curve (AUC) for QL (~170 mL, p = 0.7) during the 1 min PLM, and the increase in QL from rest to the peak response to PLM (QLΔpeak; ~540 mL/min, p = 0.3) were not different at any phase of the MC. Furthermore, MAP AUC (~1.0 mL), MAPΔpeak (~6 mmHg), and therefore leg vascular conductance (VC) AUC (~1.9 mL/mmHg) and VCΔpeak (~6.5 mL/min/mmHg), did not change throughout the MC (p > 0.3). Finally, COΔpeak (~0.6 L/min) and HRΔpeak (~7 bpm) remained similar throughout the MC (p > 0.4).SUMMARY & CONCLUSIONDespite significant differences in venous estrogen and progesterone concentrations during EF, LF, and ML, the hyperemic response to PLM was unchanged at each phase, indicating that microvascular function remain consistent throughout the MC. In addition, both the MAP and the central hemodynamic response to PLM was similar at each stage of the MC. These findings suggest that a tight control of the MC may no longer be considered critical for studies focusing on microvascular function. These new insights might, ultimately, facilitate the involvement of females in future investigations.
Maternal undernourishment stimulates fetuin‐B and impairs placental development
Authors: Camilliere Mia , Rabadi May , Khandi Sharah , Rabadi Seham , Eldana Ahmed , Rath Asha , Wolin Michael , Ratliff Brian 
Published: May 2022

Background and AimsLow birth weight (LBW) significantly increases the risk for multiple diseases, including cardiovascular and kidney diseases. Low birth weight can be caused by a variety of factors, including maternal undernourishment (MUN) during pregnancy. In our study here, we investigated the effects of MUN on the developing placenta, with particular focus on the role of oxidative stress and fetuin‐B in placental impairment.MethodsUsing a mouse model of MUN to generate LBW offspring, in which the pregnant mother consumes reduced total calories and protein during gestation, we examined placental vascularization, vascular reactivity, and blood perfusion using immunofluorescence, myograph, and laser‐doppler flowmetry, respectively. We further examined placental pathology during MUN and pharmacological intervention through histology, immunofluorescence staining and immunoblotting. Trophoblast cell cultures were also used in experiments.ResultsWe observed reduced vascular density, vascular reactivity and blood perfusion in the placenta during MUN, along with a reduction in total placental trophoblasts. Further analysis revealed that MUN significantly increases the expression and secretion of the small protein fetuin‐B in the placenta. Treatment of trophoblasts with fetuin‐B increased the activity of NF‐kB in these cells, while also stimulating their generation of reactive oxygen species. Subsequently, fetuin‐B effectively reduced trophoblast quantity by impairing their proliferative expansion, stimulating their apoptosis, and reducing their differentiation. Treatment of MUN pregnant mothers with antioxidants improved placental vascular function and helped preserve placental trophoblast pools.ConclusionMUN upregulates fetuin‐B and oxidative stress in the placenta, effects which consequently impair placental development and vascular function.
Myostatin Deletion Preserves Cardio‐Metabolic Function in Type 1 diabetes
Authors: Huff Denton R. , Nunan Emily L. , Gore Jillian L. , Wright Carson L. , Valdez Cammi , Butcher Joshua T. 
Published: May 2022

Type 1 Diabetes Mellitus (T1DM) is a disease characterized by the destruction of insulin‐secreting pancreatic beta cells and results in hyperglycemia, muscle wasting, and vascular dysfunction. Patients afflicted with T1DM suffer from increased morbidity and early mortality, largely driven by an inability to appropriately maintain glucose homeostasis. Skeletal muscle is the body’s largest metabolic reservoir, absorbing significant amounts of glucose from the bloodstream. The myokine myostatin is a potent negative regulator of muscle growth and is upregulated in T1DM patients but downregulated following regular exercise. Physical exercise is also known to improve cardiovascular health and increase insulin sensitivity of muscle, but many T1DM patients are unable to exercise at a level that conveys benefit due to muscle atrophy. Thus, directly targeting skeletal muscle, independent of exercise, may prove beneficial for T1DM therapy. Our hypothesis is that genetic deletion of myostatin will preserve glucose homeostasis, maintain muscle function, and protect against vascular dysfunction and cardiometabolic effects in a mouse model of T1DM.T1DM was induced via streptozotocin (STZ) in adult male mice with (WT) and without myostatin (MyoKO). Multiple variables were assessed including glucose homeostasis (plasma glucose, HbA1c, IGTT), fluid dynamics, muscle function (in vivo plantarflexion), and vascular function (ex vivo pressure myography of gracilis arteriole).Myostatin deletion inhibited STZ‐induced increases in plasma glucose, preserved fluid dynamics, and prevented decreases in muscle function, independent of insulin. Further, endothelial function was protected with myostatin deletion. Taken together, this data suggests that myostatin inhibition may be a target for effective treatment and management of the cardiometabolic and skeletal muscle dysfunction that occurs with T1DM.
Baroreceptor Deafferentation Impairs the Exercise Training ‐and Drug Treatment‐Induced Adaptations in a Hypertensive Model of Menopause
Authors: Ferreira Maycon J. , do Carmo Silva Gabriel , Bernardes Nathalia , de Araujo Amanda A. , da Silva Dias Danielle , Irigoyen Maria C. , De Angelis Kátia 
Published: May 2022

Aim and HypothesisHere, we investigate the effect of SAD on physical and hemodynamic adaptations after long‐term treatment with Enalapril and concurrent exercise training (CET) in a model of menopause. We hypothesized that the beneficial effects of exercise training combined with antihypertensive drug therapy would be reduced after the chronic absence of arterial baroreceptor reflex.MethodsFemale spontaneously hypertensive rats (90 days old) were distributed (7‐8 animals/group) into ovariectomized groups: trained treated with E (OTE) and SAD trained treated with E (SAD‐OTE). SAD procedure was performed at initial of protocol. Ovariectomy consisted of bilateral removal of the ovaries. Enalapril (3mg/kg) was administrated orally in drinking water. CET (40‐60% maximal capacity) consisted of aerobic (motor treadmill) followed by resistance exercises (ladder adapted to rats), 3 days/wk for 8 weeks. Heart rate and BP variability were analyzed using signals of direct recording of BP. Vasopressor system was evaluated by sequential injection of a vasopressin receptor antagonist, losartan and hexamethonium.ResultsTreadmill performance was reduced in SAD group (p<0.001). There were no differences for systolic, diastolic, and mean blood pressure (BP) between groups. SAD increased resting heart rate (p<0.001). In addition, SAD‐OTE group showed lower variance of pulse interval (ms²) (49.2±22.5 vs. OTE: 96.5±49.6), as well as higher systolic BP variance (mmHg²) (84.1±36.9 vs. OTE: 34.2±9.0) and low‐frequency band (mmHg²) (11.2±4.9 vs. OTE: 6.5±3.4). BP reduction (mmHg) after vasopressin receptor antagonist (‐20.5±10.5) and hexamethonium (‐87.2±17.7) was higher in SAD‐OTE (vs. OTE: ‐6.9±4.6 and ‐56.0±10.4, respectively).ConclusionDespite similar BP control, drug therapy‐and training‐induced adaptations are blunted in absence of baroreceptor deafferentation, suggesting that this mechanism play a crucial role to maintain physical and cardiovascular autonomic benefits.
An Exercise Mimetic Blunts Influenza‐Induced Mortality in Middle Aged and Obese Mice
Authors: Nunan Emily L. , Baker Hallie , Gammill Blake , Butcher Joshua T. 
Published: May 2022

Viral infection is well known for its ability to significantly compromise cardiovascular health, and elevate morbidity and mortality in healthy (and unhealthy) patients. Susceptibility to the consequences of viral infection are significantly elevated in the obese and aged populations. Even modest amounts of exercise are protective against influenza, influenza severity and mortality, and additionally enhance immunization efficacy in both human and rodent models. However, exercise is contra‐indicated in those with viral infection, due to potential contagiousness and a weakened immune state. Further, a significant patient population is unable to exercise at a rate that confers cardiovascular benefit (ex: the aged, obese, those constrained by a pandemic). Thus, it would be inherently valuable to determine if an exercise mimetic can protect and preserve function, independent of increases in activity or exercise. To address this question, our lab manipulates the muscle myokine myostatin (GDF‐8) in obese and aged mouse models. Myostatin is a potent negative regulator of skeletal muscle growth that is upregulated in human and animal models of obesity, influenza, and downregulated following regular exercise. Our hypothesis is that targeting myostatin in a rodent model of influenza will prevent mortality via a mechanism that mimics the benefits of exercise.Influenza infection was induced via intranasal administration of Influenza A/PR/8/34 in WT and obese (db/db) mice with and without myostatin deletion. Importantly, middle aged mice (aged 40‐60 wks) were used to appropriately mimic a susceptible human phenotype. Assessed variables included weight, survival, coat score and inflammatory factors in the lung.Myostatin deletion significantly improved survival in mice compared to infected controls, with lean controls experiencing ~27% mortality and obese controls experiencing ~50% mortality. No mortality was observed in obese and lean groups with myostatin deleted. All groups experienced similar weight loss, demonstrating effective influenza infection. Lung inflammatory factors showed significantly elevated IL‐2, MCP‐1, and IL1b in infected lean myostatin KO mice, as well as NOX1 and NOX2, compared to infected controls. Taken together, our data suggests that myostatin may be an effective target for improving outcomes in influenza infection.
Amyloid‐Beta Precursor Protein: Essential to Lung Capillary Barrier Defense During Acute Infection
Authors: Voth Sarah B. , Choi Chung‐Sik , Morrow K. A. , Gwin Meredith S. , Knighten Jennifer , Francis C. M. , Lin Mike T. , Gautam Samir , Frank Dara W. , Audia Jonathan P. , Stevens Troy , Sharma Lokesh , Cruz Charles D. 
Published: May 2022

RationalePneumonia is a leading cause of acute respiratory distress syndrome (ARDS) and sepsis. Despite resolution of active infection, pro‐inflammatory mediators and cytotoxins elicited during the acute phase promote secondary tissue injury, impede recovery, and contribute to poor patient prognoses. Lung infection with Pseudomonas aeruginosa, Klebsiella pneumoniae, and influenza elicit pathogenic amyloids that propagate injury and likely contribute to this inflammatory milieu. However, clinical trials targeting amyloid‐beta (Aβ) have consistently failed. Lung endothelial‐derived amyloids have been implicated as innate antimicrobial effectors yet the contribution of Aβ to host defense of the lung capillary barrier remains poorly resolved. We hypothesized that lung endothelial Aβ contributes to 1) the attenuation of active infection, and 2) endothelial barrier resilience to infection.MethodsTo test our hypotheses, CRISPR/Cas9 was targeted to Aβ precursor protein (APP) in rat pulmonary microvascular endothelial cells (PMVECs), and the deletion was confirmed via PCR, sequencing, and immunoblotting. The contribution of APP expression to cell proliferation, self‐replication, wound closure, angiogenesis, and barrier integrity (transwell permeability, bacterial dissemination, ECIS) both at baseline and during virulent infection was assessed in both WT and APP‐/‐ PMVECs. Amyloid content was monitored with immunoblotting and Thioflavin T staining. Antimicrobicity was measured with kinetic bactericidal assays, agglutination, plating, and SYTO 9/propidium iodide.ResultsAPP‐/‐ cells were ~49% less effective in reducing the bacterial load of an active infection as compared to APP expressing PMVECs. Immunodepletion of Aβ from WT endothelial cell supernatant reduced bactericidal efficacy in a comparable manner. APP‐/‐ cells also exhibited impaired proliferation (WT: 0.59 days, APP‐/‐ 0.91 days), a ~2.2‐fold reduction in replication capacity, poor wound closure and barrier formation, and little resilience to infection with loss of barrier integrity in roughly half the time of infected WT PMVECs. Moreover, conditioning of naïve cells with supernatant derived from WT but not APP‐/‐ PMVECs significantly increased proliferation and angiogenic capacity.ConclusionsLung endothelial APP is an important contributor to host defense. Both APP and its Aβ variant(s) appear to constrain infective bacterial burden whereas APP products appear to function as mitogens/morphogens within the microvascular milieu, likely contributing to tissue repair and recovery post‐insult.
Comparison Of Dynamic Calcium Signaling Profiles On Activation Of TRPV4 Channel And T‐Type Calcium Channel In Pulmonary Microvasculature
Authors: Sen Pallavi , Choi Chung‐Sik , Taylor Mark 
Published: May 2022

BackgroundAcute Lung Injury (ALI) is characterized by inflammation, barrier disruption and edema within lung microvasculature. A dysregulation in intercellular signaling of calcium (Ca2+) within pulmonary microvascular endothelium potentially damages lung endothelial barrier integrity. Recently, two plasma membrane ion channels, the vanilloid transient receptor potential IV (TRPV4) and the T‐type voltage gated calcium channels (TTCC) have been implicated as potential conduits for spatially and temporally targeted Ca2+ signals within lung endothelium. Ca2+ entry via TRPV4 causes barrier disruption and Ca2+ entry via TTCC regulates P‐selectin expression, but their underlying patterns of specific Ca2+ signaling events are unknown. Therefore, in this study we aim to determine whether these channels elicit distinct Ca2+ signaling events that might contribute to their different functions in lung endothelium.MethodPulmonary microvascular endothelial cells (PMVECs) grown in 35mm glass‐bottomed dishes were loaded with fluorescent Ca2+ indicator Cal‐520 AM and recorded for signals via spinning disk confocal microscopy. After baseline recording, cells were subjected to GSK1016790 (TRPV4 activator) and then to GSK2798754 (TRPV4 inhibitor). Another set of cells were treated with high K+ solution (TTCC activator) and then with mibefradil (TTCC inhibitor). Lung slices were mounted on Sylgard inserts, and loaded with Cal‐520 AM. Two different slices were recorded for baseline activities and were respectively subjected to same drug treatments as PMVECs. Time‐lapse image sequences recorded after each addition were analyzed for amplitude and frequency of events using ImageJ and customized signal detection software LC_Pro.ResultsIn PMVECs with TRPV4 channel activation, the amplitude and frequency of events increased 1.5‐fold when compared to baseline, whereas the TTCC activation showed an increase by 1.3‐fold. In lung slices, the TRPV4 channel activation exhibited an increase by 1.4‐fold compared to baseline, as opposed to an increase of only 1.1‐fold with TTCC activation. The addition of respective inhibitors brought the signals back to near baseline levels.ConclusionOur findings suggest both TRPV4 channel and TTCC activation caused an increase in Ca2+ dynamics, with the TRPV4 channel activation showing a greater increase in event amplitude and frequency than TTCCs, thereby indicating they both contribute to distinct signaling events in PMVECs and lung slices. Further studies will focus on how these different signatures contribute to the differential functional roles of the channels.