bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local Angiotensin 1–7 Administration Augments Microvascular Endothelial Function in Women Who Have Had Preeclampsia
Authors: Stanhewicz Anna , Alexander Lacy 
Published: June 2021

Women with a history of preeclampsia are at increased risk of developing cardiovascular disease. Despite remission of the clinical symptoms of preeclampsia postpartum, women who have had preeclampsia demonstrate microvascular endothelial dysfunction, mediated in part by increased sensitivity to angiotensin II. Angiotensin 1–7 (ang 1–7) is an endogenous inhibitor of the actions of angiotensin II and therefore a biologically plausible target for improving endothelial function in postpartum women who have had preeclampsia. Using the cutaneous microcirculation as a model, we hypothesized that women who have had preeclampsia (PreEC) would have attenuated endothelium‐dependent‐ and reduced nitric oxide (NO)‐dependent vasodilation compared to control women who had a normal pregnancy (HC). We further hypothesized that localized ang 1–7 administration would increase endothelium‐dependent vasodilation and NO‐dependent vasodilation in PreEC, but not HC. The subject sample included 8 PreEC (26±2 yrs of age; 6±2 months post‐partum) and 7 HC (32±2 yrs; 6±1 months post‐partum). Four intradermal microdialysis fibers were placed in the skin of the ventral forearm for the graded infusion of acetylcholine (ACh, 10−7 – 102 mM), ACh + 15 mM NG Nitro‐L‐arginine methyl ester (L‐NAME; nitric oxide synthase antagonist), ACh + 100μM ang 1–7, or ACh + 15 mM L‐NAME + 100μM ang 1–7. Red cell flux was measured over each site by laser‐Doppler flowmetry (LDF). Cutaneous vascular conductance was calculated (CVC=LDF/MAP) and normalized to the respective site‐specific maximum (%CVCmax; 28 mM SNP + local heating to 43°C). ACh‐induced vasodilation was attenuated in PreEC compared to HC (logEC50: −1.0±0.2 vs. −1.8±0.1; p=0.04). There was no difference between PreEC and HC when ACh was co‐infused with L‐NAME (PreEC logEC50: −0.9±0.3 vs. HC: −1.2±0.2 logEC50). ACh + Ang 1–7 co‐infusion augmented the vasodilation response in PreEC (logEC50: −1.9±0.1) compared to ACh alone (logEC50: −1.0±0.2) (p<0.001) but had no effect in HC. Co‐infusion of ang1–7 + L‐NAME + ACh did not differ from ACh + L‐NAME in either group. Women who have had preeclampsia demonstrate attenuated endothelium‐dependent and NO‐dependent vasodilation compared to women who have had a healthy pregnancy. Ang 1–7 increased endothelium‐dependent vasodilation via NOS‐mediated pathways in women who have had preeclampsia, suggesting that ang 1–7 may be a viable therapeutic target for improved microvascular endothelial function in women who have had a preeclamptic pregnancy.Support or Funding InformationNIH F32 HL129677‐03 (Stanhewicz), R01 HL093238‐07 (Alexander)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Protective Effects of Diet and Sex on Cell Death and Intracellular Calcium in Resistance Arteries during Oxidative Stress
Authors: Norton Charles E. , Sinkler Shenghua Y. , Manrique Camila M. , Segal Steven S. 
Published: June 2021

Reactive oxygen species are implicated in vascular dysfunction and the development of cardiovascular disease. However, chronic exposure to oxidative stress during advanced age protects endothelial cells (ECs) of the superior epigastric artery (SEA) in male mice from hydrogen peroxide (H2O2)‐induced Ca2+ entry and cell death (PMC4422569), and we have found similar protection in SEA smooth muscle cells (SMCs). We hypothesized that a Western style diet (WD) high in fat and fructose, by promoting chronic oxidative stress, would also improve vascular cell survival during exposure to H2O2. Because females appear more resilient to oxidative stress compared to males, we also investigated the effect of sex on cell death and intracellular calcium ([Ca2+]i) with WD. Male and female C57BL/6 mice (age, 4 weeks; n=4–5/group) were fed WD (TestDiet 58Y1; calories: 46% fat, 17.5% sucrose, 17.5% high fructose corn syrup; 19% protein), or Standard diet (Formulab Diet 5008; calories: 17% Fat, 56% carbohydrate, 27% protein) for 20 weeks. A mouse was then anesthetized (isoflurane) and the SEA (inner diameter, 100–150 μm) was isolated, pressurized to 100 cm H2O in physiological salt solution (pH 7.4, 37°C), and exposed to H2O2 (200 μM) for 50 minutes. Hoechst 33342 (1 μM) stained nuclei of all cells while propidium iodide (2 μM) stained nuclei from dead cells; SMC nuclei (n=121±3 per SEA) were oriented perpendicular to the vessel axis and EC nuclei (n=125±2 per SEA) were oriented parallel to the vessel axis. With Standard diet, SEAs from males had greater (P<0.05) cell death (SMCs=21±1%, ECs=6±1%) versus SEAs from females (SMCs=9±2%, ECs=2%). Consuming WD attenuated SMC death in SEAs from both males (to 11±6%) and females (to 3±1%) (P<0.05 for each) as well as in ECs from males (to 2%) with no further effect in ECs from females (2%). Because an aberrant rise in [Ca2+]i can initiate cell death, [Ca2+]i responses to H2O2 were evaluated using Fura‐2 fluorescence (F340/F380 ratios). With no effect of diet or sex on [Ca2+]i at rest, H2O2 increased [Ca2+]i in SEAs from males fed Standard diet (ΔF340/F380=0.57±0.04) by an 8‐fold greater (P<0.05) extent than in SEAs from females (ΔF340/F380=0.07±0.05). SEAs of males fed a WD exhibited a reduced [Ca2+]i response to H2O2 (ΔF340/F380=0.45±0.08) (P<0.05), however this effect of diet was not observed in SEAs of females (ΔF340/F380=0.19±0.06). We conclude that ECs and SMCs in resistance arteries of females are more resilient to acute H2O2 exposure compared to males and that WD promotes resilience to oxidative stress most effectively in males.Support or Funding InformationNIH R37HL041026; 5K08HL129074This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Roles of Cell‐Cell Junction and Substrate Stiffness in Determining 3D Forces of Endothelial Cells
Authors: Hur Sung Sik , Yeh Yi‐Ting , Lee Kyunghang , Wang Yuanjia , Li Yi‐Shuan , Chien Shu 
Published: June 2021

Mechanical forces play an important role in regulating structure and functions of cells, including motility, proliferation, and survival. The integrity of cell‐cell junction is crucial in the physiological behavior of endothelial cells. Thus, it is essential to understand the modulation of endothelial cells by their micro‐environment such as substrate stiffness, confluency, and cell‐cell junction.We have developed three‐dimensional traction force microscopy (3D‐TFM) and intracellular force microscopy (3D‐IFM) to measure cell‐ECM, cell‐cell, and intracellular stresses of live cells in three dimensions at the subcellular level. These novel methods have been applied in order to investigate the mechanical responses of endothelial cells to changes in substrate stiffness, cell confluency, and cell‐cell junction. The results indicate that endothelial cells exhibit differences in the magnitude and spatial distribution of mechanical behaviors (traction and intracellular stress) and morphological features (area and aspect ratio) in response to substrate stiffness (1.5 kPa and 10b kPa hydrogel), cell confluency (existence of cell‐cell junction), and junction‐affecting drugs (thrombin and angiopoietin).We have shown that biophysical and biochemical environments are important in the control of endothelial cell structure and function. Studying how the forces are regulated spatially and temporally at the subcellular level in response to changes of cellular microenvironment can lead to further understanding of the physiology of endothelial cells and pathogenesis of vascular diseases.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Estrogen receptor alpha mediated activation of the endothelial epithelial sodium channel: role in the genesis of arterial stiffness
Authors: Manrique Camila , Yang Yan , Lising Alexander , Chen Dongqing , Aroor Annayya , Sowers James R. , Hill Michael 
Published: June 2021

Premature arterial stiffening is often seen in obesity and type 2 diabetes (T2D). Although both men and women are affected, T2D women are at greater risk. As augmented arterial stiffness is an independent predictor of cardiovascular disease, the increased susceptibility of women to arterial stiffening may explain their higher overall risk. In healthy females, estrogen signaling prevents stiffening, but these effects are blunted in obesity where signaling via estrogen receptor alpha (ERα) appears deleterious. We have previously reported that deletion of ERα in endothelial cells (EC) results in decreased arterial stiffening in conditions of over‐nutrition and insulin resistance. Importantly, the EC epithelial sodium channel (ENaC) has been hypothesized as a central mediator in the genesis of endothelial dysfunction and arterial stiffness, and estrogen has been shown to activate ENaC activation. Here we examine the preferential activation of the EC ENaC in females under conditions of insulin resistance and the role of estrogen signaling, specifically via ERα, on the activation of the EC ENaC. In the present investigation we report that cultured aortic EC from female mice exhibited a significant increase in amiloride‐sensitive sodium currents (ENaC currents) assessed by patch‐clamp after treatment with 100 nM 17beta‐estradiol (E2) for 24 hours when compared to control. In contrast, there was no significant effect of E2 treatment on ENaC currents in EC from male mice. Further, we found that C57BL6/J female mice fed for 16 weeks with a diet high in fat and high in fructose (WD; TestDiet 58Y1; calories: 46% fat, 17.5% sucrose, 17.5% high fructose corn syrup; 19% protein) exhibit augmented aortic endothelial surface stiffness assessed via atomic force microscopy when compared with male mice. Moreover, primary lung ECs from female mice fed WD exhibited elevated E2‐stimulated ENaC currents when compared with control fed female mice and with male mice. In addition, in primary ECs isolated from female EC‐specific ERα knockout mice there was a significant abrogation of the E2‐stimulated amiloride sensitive sodium currents without significant changes in aldosterone (10 uM) induced sodium currents. Our results show that in conditions of over‐nutrition, there is enhanced EC ENaC activation and highlights the important role of estrogen, via ERa signaling, as a modulator of the expression and activity of the EC ENaC. Future studies will determine the direct impact of ERα‐mediated activation of ENaC in the genesis of arterial stiffness in obesity and T2D.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Arterial dysfunction displayed by old mice with repressed endothelial cell autophagy is rescued by pharmacological activation of purinergic 2Y1 receptors
Authors: Kwon Oh Sung , Cho Jae Min , Park Seul‐Ki , Bharath Leena Panneerseelan , Richardson Russell S. , Anandh Pon Velayutham Babu , Boudina Sihem , Symons J David 
Published: June 2021

Earlier we reported that genetic repression of endothelial cell (EC) autophagy impairs autocrine signaling via the purinergic 2Y1 (P2Y1) receptor to EC nitric oxide (NO) synthase (eNOS), and prevents NO generation in response to shear stress. Herein we sought to determine whether aging‐associated endothelial dysfunction displayed by mice with defective vascular autophagy could be restored by promoting purinergic signaling. First, mRNA and protein expression of autophagy markers was lower in ECs and arterial homogenates of 22–23 month old (old) vs. 6–7 month old (adult) mice. Second, the ability of aged mice with repressed basal autophagy to upregulate this process in response to physiological stimuli was prevented. Specifically, 14 h fasting and 60‐min treadmill‐running increased autophagy in arteries from adult but not old mice. Third, autophagy suppression (3‐methyladenine) impaired flow‐mediated vasodilation in arteries from adult mice evaluated ex vivo, while autophagy activation (trichostatin‐A) preserved vasodilation in arteries from older animals. Finally, the selective P2Y1 receptor agonist 2‐methylthio‐ADP restored arterial function in arteries from aged mice whereas P2Y1 receptor inhibition using MRS2179 precipitated an aging phenotype in vessels from adult animals. We provide the first evidence that aging : (i) prevents the autophagic response to fasting and acute exercise and (ii) attenuates flow‐mediated vasodilation in a manner that can be restored by intervening distal to defective vascular autophagy i.e., by pharmacological promotion of purinergic autocrine signaling. Further research concerning the G protein‐coupled P2Y family of receptors is warranted in an effort to explore new therapeutic treatment options for aging‐related endothelial dysfunction that is secondary to defective EC autophagy.Support or Funding InformationAHA 16GRNT31050004, NIH RO3AGO52848, Seed Grants from the UU Office of the Vice‐President for Research, the UU College of Health, the UU Center on Aging, the UU Diabetes and Metabolism Center, and the Diabetes Research Center at Washington University at Saint Louis 5 P30 DK020579 (JDS)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Enhanced Blood Pressure Lowering Responsiveness with Endocrine‐Sympathoinhibitory Electroacupuncture in Middle‐Aged Hypertensive Women
Authors: Tjen‐A‐Looi Stephanie , Xie Lifang , Fu Liang‐Wu , Li Peng , Malik Shaista 
Published: June 2021

Our recently published study shows that 8‐week electroacupuncture (EA) at P5–6 and ST36–37 reduces blood pressure (70% responsiveness, blood pressure decrease of ≥ −6 mmHg) and sympathetic activity in a group of male and female (38–75 year) patients with mild to moderate hypertension (HTN). They were off of antihypertensive medications. Blood pressure reduction with 30‐min EA once a week treatment was observed by week 4. After 8 weeks of EA sessions, the blood pressure reduction lasted for at least a month. Here we define treatment at P5–6+ST36–37 as the sympathoinhibitory EA. Interestingly, the majority (64%) of middle‐aged women with HTN were not responsive to this treatment that reduces sympathetic activity. To this end, we formulated a targeted treatment towards middle‐aged perimenopausal hypertensive women. We hypothesized that endocrine‐sympathoinhibitory EA treatment decreases blood pressure in majority of middle‐aged perimenopausal females with mild to moderate HTN. Eleven enrolled women ages 49 to 66 year with hypertension were randomly assigned to sympathoinhibitory EA treatment (P5–6+ST36–37, n=6) or endocrine‐sympathoinhibitory EA treatment (P6+LI4+ST36+Sp6+CV3–4+LR3+KI3, n=5). Participants were not on antihypertensive medications and hormonal therapy. The enrolled patients have completed the 8‐week course of treatment. The blood pressure lowering responsiveness (≥ −6 mmHg) to endocrine‐sympathoinhibitory EA was 80% while only 33% of the subjects treated with sympathoinhibitory EA lowered their blood pressures. Peak systolic blood pressure (SBP) during 24 hours dropped from 177±7.4 to 160±5.0 mmHg (P=0.033) while averaged 24‐hour SBP dropped from 144±3.3 to 134±2.5 mmHg (P=0.036) in 5 subjects treated with endocrine‐sympathoinhibitory EA. The peak mean blood pressure (MBP) tended to decrease with P value of 0.065 in 5 subjects. On the other hand, 8‐week course of sympathoinhibitory EA treatment did not decrease SBP, MBP, peak SBP and peak MAP in 6 subjects. Thus, endocrine‐sympathoinhibitory EA in middle‐aged hypertensive women may enhance blood pressure lowering responsiveness compared with sympathoinhibitory EA treatment.Support or Funding InformationAdolf Coors FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
A Novel Role for Sox6 in Renin Expression Control During Renal Artery Stenosis Induced Hypertension
Authors: Gomez Jose A. , Saleem Mohammad , Xiao Liang , Horton Kandi D. , Hodgkinson Conrad P. 
Published: June 2021

Study ObjectiveWe wanted to determine if the transcription factor Sox6 played a role in renin expression control and in the hypertension induced by renal artery stenosis. In renal artery stenosis, renin is a key disease driver. Renin catalyzes the rate limiting step in the Renin Angiotensin Aldosterone System (RAAS); converting angiotensinogen to angiotensin I. We used a novel transgenic mouse (Ren1dCre/Sox6fl/fl) to determine the impact of specific Sox6 ablation in renin expression during JG cell expansion and renal artery stenosis renal induced hypertension.MethodsIn vivo: JG cell expansion was induced by 10 days of low sodium diet (0.01% Na) and furosemide (0.1 mg/g body weight). Renal artery stenosis was induced by the 2 Kidney 1 clip (2K1C) Goldblatt model; renin is overexpressed in the clipped kidney with renin expression being repressed in contralateral kidney. In vitro: primary renal Mesenchymal Stromal Cells (MSC) were isolated from wild‐type mice. MSC were differentiated into renin expressing cells by 7 days I&F (3‐isobutyl‐methyl‐xanthine (IBMX)‐100 uM and Forskolin‐10 uM) treatment.ResultsI&F induced renin expression in MSCs (Renin relative expression to gapdh 0.0153±0.005, n=3, P= 0.05, no renin expression in control MSCs). In the Ren1dCre/Sox6fl/fl there was no difference in blood pressure or heart rate at base line. However, under conditions that promote JG cell expansion, Sox6 ablation halted the increase in the number of JG cells (8.75 fold decrease, n= 6 to 9, P= 0.001). In our preliminary study we found that specific knock‐out of Sox6 in renin expressing cells protected the kidney against renal artery stenosis injury when compared to control mice (two mice per group). After renal artery stenosis, wild‐type kidneys were one‐third the size of Ren1dCre/Sox6fl/fl kidneys. In addition, renin expression was ~50% higher in the wild‐type group.ConclusionOur data indicates that Sox6 plays a novel role in renal physiology; modulating renin expression during pathological conditions. These results will aid in the discovery of a novel transcriptional regulatory network controlled by Sox6, involved in blood pressure regulation. Identification of this novel pathway and its regulators may lead to new therapies for blood pressure control aiming at decreasing cardiovascular disease in hypertensive patients.Support or Funding InformationResearch was supported by American Heart Association Scientist Development Award to JAG (16SDG29880007), the Vanderbilt University Medical Center Faculty Research Scholars Program, and NHLBI Research Scientist Development Grant 1K01HL135461‐01 to JAGThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Prospective Study To Investigate The Prevalence Of The 90 kDa Isoform Of Angiotensin Converting Enzyme In Vitória ‐ Brazil
Authors: Gomes Andreia Cristina , Fernandes Fernanda Barrinha , do Carmo Franco Maria , Mill Jose Geraldo Carmo , Casarini Dulce Elena 
Published: June 2021

Hypertension is considered a worldwide public health problem and identified as a risk factor for cardiovascular morbidity and mortality. The Renin Angiotensin System (RAS) has been a focus of interest of researchers in the area of hypertension both for the identification of its etiopathogenesis and for its treatment. In order to identify the components involved in the onset of hypertension and the participation of Angiotensin I Converting Enzyme (ACE) in this problem, the RAS has been the object of many studies. ACE has a great physiological importance for converting angiotensin I (Ang I) to angiotensin II (Ang II), a potent vasoconstrictor. Some papers suggest the association of ACE isoforms, especially the 90 kDa isoform, with hypertension. The aim of this study was to investigate the association between ACE isoforms and the presence of arterial hypertension in the second phase of the prospective study (MONICA Project) in the population of Vitória ‐ ES, Brazil.MethodsThe demographic, clinical and biochemical parameters of 220 individuals were evaluated. Urine samples were concentrated and ACE isoforms were identified by the Western Blotting technique.ResultsThe groups were classified as Group 1 (presence of isoforms with 65, 90 and 190 KDa); Group 2 (presence of 65 and 90 kDa isoforms) and Group 3 (presence of 65 and 190 kDa isoforms). The results showed a high prevalence of the 90 kDa isoform with a higher incidence of hypertension (higher in group 2) after five years of segment. The groups containing 90 kDa isoform showed higher systolic and diastolic pressure profiles in the second phase and the frequency of normotensives expressing the isoforms with 65 and 190 kDa was higher than that the hypertensive ones. Loss of isoform expression at 190 kDa increases the chances of developing hypertension as well as family history of hypertension.ConclusionThe results suggest the 90‐kDa N‐domain isoform as a possible biological marker of hypertension, which confirms the results obtained in the first phase of the study.Support or Funding InformationCNPq and FAPESPThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CNS‐Specific Leptin Receptor Deficiency Impairs Cardiac Reserve
Authors: Gava Fabio N. , Moak Sydney P. , do Carmo Jussara M. 
Published: June 2021

We previously showed that leptin deficiency leads to reduced myocardial reserve independent of changes in body weight, and that leptin replacement in non‐obese ob/ob mice completely restored ejection fraction (EF) responses to a cardiovascular stress test. Whether central nervous system (CNS) leptin receptor (LepR) activation contributes to normal myocardial reserve during increased cardiac stress is unknown. In this study we examined if deletion of LepR specifically in the CNS alters cardiovascular responses to a stress test induced by dobutamine in 22 week old mice. LepR/Nestin‐Cre mice with LepR deleted in the CNS were generated by breeding LepRflox/flox mice with Nestin‐Cre mice. Male LepR/Nestin‐Cre (n=4) and WT control (n=5) mice were instrumented for continuous infusion of saline and progressively increasing doses of dobutamine (2–12 ng/g body wt/min, 2 min at each dose). Long and short axis left ventricle dimensions were obtained before and one minute after each dose of dobutamine using a 30 MHZ transducer (VEVO2100®). Compared to WT, LepR/Nestin‐Cre mice were heavier (73±3 vs 34±1 g) due to hyperphagia (5.5±0.5 vs 3.8±0.5 g food/day), normoglycemic (174±10 vs 180±11 mg/dL), hyperleptinemic (109±1.5 vs 6.5±0.9 ng/mL), and hyperinsulinemic (119±23 vs 10±3 mU/mL). Baseline heart rate (HR) was similar in LepR/Nestin‐Cre (433±16 bpm) and WT (421±28 bpm) mice. Baseline EF was significantly higher in LepR/Nestin‐Cre (80±2%) compared to WT (66±4%) mice. Dobutamine infusion (4 ng/g/min) decreased average HR by 47±15 in LepR/Nestin‐Cre and increased HR by 41±11 bpm in WT mice. Dobutamine increased EF by 28±5% in WT mice but no significant change (4±4%) occurred in LepR/Nestin‐Cre mice. These results show that despite significant increases in plasma leptin concentration and presumably stimulation of cardiac LepR, CNS LepR deficiency leads to reduced myocardial reserve in response to a cardiovascular stress test in male mice. (NHLBI‐PO1HL51971, NIGMS P20GM104357)Support or Funding InformationNHLBI‐PO1HL51971, NIGMS P20GM104357This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.