bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of vascular endothelial and smooth muscle cell pathways and their contributions to myogenic and agonist‐mediated control (677.16)
Authors: Pradhan Ranjan , Lee Pilhwa , Beard Daniel , Carlson Brian 
Published: June 2021

Vascular smooth muscle cell contraction and relaxation is central to the local regulation of blood flow to tissue. At the arteriolar level, interactions between vascular endothelial cells and smooth muscel cells play critical role in determining the level of vascular tone. During mechanical and/or agonist stimulations, vascular Ca2+ dynamics are finely adjusted via a number of signaling pathways and the Ca2+ levels in the smooth muscle cells determine the level of contraction. To quantify how cellular Ca2+ dynamics are transformed into changes in vascular tone, we have constructed a cellular‐based model of isolated resistance vessel by integrating models of vessel wall mechanics, smooth muscle force generation, smooth muscle Ca2+ handling and electrophysiology with an endothelial electrophysiology and Ca2+ handling model. The dose‐response vasodilation and vasoconstriction data of different sizes of vessels in response to pharmacological vasoconstrictors and vasodilators, measured using a novel isovolumic myograph developed by Lu and Kassab are analyzed. The model simulates how changes in intraluminal pressure are used to maintain a constant vessel diameter during application of phenylephrine and acetylcholine. In order to simulate these sets of experimental data the model captures integrated vessel behavior including ionic (Ca2+, K+, Na+, etc.), IP3 and nitric oxide myoendothelial transport. Model analysis shows that α‐adrenergic pathways in smooth muscle and NO pathways in endothelium are sufficient to capture the experimentally observed phenylephrine and acetylcholine mediated responses.Grant Funding Source: NIH U01 HL118738, NSF CBET 1133260 and NIH P50‐GM094503
Hemodynamic consequences of spatially‐dependent sympathetic regulation in skeletal muscle arteriolar trees (678.14)
Authors: Al‐Khazraji Baraa , Saleem Amani , Goldman Daniel , Jackson Dwayne 
Published: June 2021

The sympathetic nervous system (SNS) elicits vasoconstriction on skeletal muscle arterioles via release of neurotransmitters norepinephrine (NE; acting on α1‐ and α2R), neuropeptide Y (NPY; acting on Y1R), and adenosine‐triphosphate (ATP; acting on P2X1R). Previous studies have shown that the level of α‐adrenoreceptor modulation is dependent on vessel branch order. However, to date, no studies have investigated the integrated roles of α1R, α2R, Y1R, and P2X1R modulation on arteriolar network hemodynamics. Thus, we evaluated the effects of phenylephrine (PE; α1R agonist), UK 14,304 (UK; α2R agonist), NPY, and ATP on arteriolar diameters in continuously branching arteriolar trees (1st order to 5th order; 1A‐5A). In male rats, concentration‐response curves (PE and ATP: 10‐9‐10‐4M; UK: 10‐9‐10‐5M; NPY: 10‐13‐10‐8M) of arteriolar diameter changes were evaluated in the gluteus maximus muscle (n蠅5 rats/group). Like others, we observed that α1R and α2R control is greatest at large (1A‐2A) arterioles, with declining sensitivity in subsequent branch orders approaching capillaries. Beyond this, we have observed that NPY and ATP elicit the greatest constrictor effects in arterioles closest to capillaries, with declining effects in descending branch orders approaching feed arterioles. Using our theoretical flow model, simulations assessed total flow and red blood cell (RBC) flow heterogeneity within the network using our experimental pharmacological data. Using our experimental inputs, we are the first to illustrate that spatial differences in ligand sensitivity enable the SNS to modify bulk tissue blood flow and RBC distribution differentially in branching networks.Grant Funding Source: NSERC
Interleukin‐1β induces brain microvascular endothelial cell hyperpermeability through matrix metalloproteinase‐9 (678.17)
Authors: Alluri Himakarnika , Anasooya Shaji Chinchusha , Wiggins‐Dohlvik Katie , Oakley Ryan , Stagg Hayden , Davis Matthew , Tharakan Binu 
Published: June 2021

Interleukin‐1β induces Brain Microvascular Endothelial Cell Hyperpermeability through Matrix metalloproteinase‐9 Himakarnika Alluri, Chinchusha Anasooya Shaji, Katie Wiggins‐Dohlvik, Ryan Oakley, Hayden W. Stagg, Matthew L. Davis, Binu Tharakan. Surgery, Texas A&M University Health Science Center & Baylor Scott and White Health, Temple, TX, USA.Brain microvascular hyperpermeability is a major contributor of vasogenic brain edema that occurs following traumatic and ischemic injuries and involves upregulation of interleukin‐1 beta (IL‐1β). Our objective was to determine if IL‐1β mediates blood‐brain barrier (BBB) hyperpermeability via Matrix Metalloproteinases (MMPs)‐induced tight junction (TJ) disruption. Rat brain microvascular endothelial cell (RBMEC) monolayers were exposed to various concentrations of IL‐1β and the optimal concentration and time to induce permeability were determined. RBMEC monolayers were exposed to IL‐1β alone or following an MMP inhibitor (GM6001; 1hour) and MMP‐9 siRNA. MMP‐9 activity was measured following IL‐1β exposure. TJ integrity and cytoskeletal assembly were studied using zonula occludens‐1 (ZO‐1) immunofluorescence and rhodamine phalloidin staining for f‐actin respectively. IL‐1β increased monolayer permeability and MMP‐9 activity significantly (p<0.05) and induced TJ disruption and actin stress fiber formation. GM6001 and MMP‐9 siRNA attenuated IL‐1β‐induced hyperpermeability significantly (p<0.05). An MMP‐9 specific inhibitor (MMP inhibitor‐1) protected both TJ integrity and actin cytoskeletal assembly. These findings suggest that up‐regulation of IL‐1β promotes activation of MMP‐9 leading to BBB breakdown and microvascular hyperpermeability.
Aerobic exercise training enhances hydrogen peroxide mediated flow induced dilation of resistance arteries following exertion in overweight adults (678.8)
Authors: Robinson Austin , Szczurek Mary , Bian Jing , Phillips Shane 
Published: June 2021

Exercise training protects against exertion‐induced microvasculature dysfunction. The purpose of this study was to determine if aerobic exercise training (AT) in overweight adults confers a protective effect. We hypothesized 1) that AT is protective and 2) H2O2 mediates this effect against microvasculature dysfunction. Eleven normotensive, overweight and obese adults (BMI 蠅25) enrolled in AT (30‐40 min. at 75% HRmax; 3 x per week) for 8 weeks, with a matched control group. Gluteal biopsies were performed at rest and following exertion at wk. 8 (6‐8 sets leg press at 10RM). Resistance arteries (RAs) were dissected from biopsies and cannulated for measures of reactivity to flow and acetylcholine induced dilation (FID; ACh) with and without the H2O2 scavenger, PEG‐CAT (500 U/ml) or the NOS inhibitor L‐NAME (10‐4 M). Nitric oxide (NO) and H2O2 production in RAs was assessed via fluorescent microscopy. FID and ACh dilations were impaired following exertion in control subjects. In contrast, FID and ACh were preserved following exertion in AT. PEG‐CAT significantly reduced FID (59 ± 8%; P< 0.01) and AChD (66 ± 6%; P< 0.01 post exertion in the AT group. Flow‐ induced NO was reduced and H2O2 production was increased in RAs of the AT subjects following exertion (H2O2:NO ↑ 2.4fold P< 0.05). We conclude that 1) AT is protective against exertion induced microvasculature dysfunction and 2) H2O2 contributes to this protective effect.Grant Funding Source: Supported by NHLBI K23HL85614, RO1HL095701, and HL095701‐01A2S
Vitamin D attenuates proangiogenic properties of pericytes through increased production of VEGF (679.1)
Authors: Jamali Nasim , Sorenson Christine , Sheibani Nader 
Published: June 2021

Retinal neovascularization is associated with pathogenesis of several major eye diseases including retinopathy of prematurity. Vitamin D compounds inhibit the growth of a variety of tumors perhaps through inhibition of angiogenesis. We showed that the active form of vitamin D, calcitriol (1, 25‐dihydroxyvitamin D3), is a potent inhibitor of retinal neovascularization during oxygen‐induced ischemic retinopathy. However, the identity of the molecular mechanisms and cellular targets remain unknown. We showed that calcitriol did not affect pro‐angiogenic properties of endothelial cells (EC). Pericytes (PC), play important roles during angiogenesis, vascular maturation and stabilization of newly forming blood vessels. Here we investigated the impact of calcitriol on retinal PC function. We show that PC express significantly higher level of vitamin D receptor compared with EC, and that calcitriol decreased proliferation and migration of PC, and caused G0/G1 arrest without affecting apoptosis. We also observed alterations in PC adhesion and expression of various matrix proteins. In addition, PC in the presence of calcitriol expressed increased level of VEGF, and antagonism of VEGF signaling by soluble VEGF‐R1 (sFlt‐1) restored proangiogenic properties of PC incubated with calcitriol. Together, our results suggest an important role for PC as target of vitamin D action and attenuation of angiogenesis.Grant Funding Source: Supported by: RC4 EY021357, P30 EY016665, P30 CA014520, RPB, ADA 1‐10‐BS‐160, and RRF
Estrogen may protect female Akita mice against development of type I diabetes and parasympathetic dysfunction of the heart (680.16)
Authors: Jin Hongwei , Georgescu Serban , Naggar Jack , Welzig Michael , Aronovitz Mark , Zhang Yali , Park Ho‐Jin , Galper Jonas 
Published: June 2021

Male Akita mouse harboring a mutation in the Ins‐2 gene, is an established animal model for the secondary effects of type I diabetes. Beginning around 3‐4 weeks of age male Akita mice develop marked hyperglycemia, hypoinsulinemia, polydipsia and polyuria. Female Akita mice develop a moderate hyperglycemia after sexual maturation. Ovariectomized (Ovx) female Akita animals implanted with a placebo (P) or 17β‐estradiol (E2) pellet were compared with the Sham‐operated female Akitas (Sham) or wild‐type (WT) mice. After 13 weeks, blood glucose increased from 268±24 mg/dl in Sham to 536±27 mg/dl in Ovx+P (mean±SEM, p<0.01) while decreasing significantly in Ovx+E2 to 125±5 mg/dl, compared to the WT (130±4 mg/dl). Compared with Sham, the Ovx+P group demonstrated increased polydipsia, glycosuria and proteinuria which disappeared completely in the Ovx+E2 group. Furthermore, Ovx+P diabetic mice demonstrated a significant decrease in the negative chronotropic response to carbamylcholine when compared with WT and Sham animals, as characterized by a smaller drop in the response to carbamylcholine (309±14 beats in Ovx+P vs. 406±11 beats in WT and 359±17 beats in Sham; p<0.01) and a decreased duration of bradycardia (4.9±0.5 min. in Ovx+P vs. 26.4±3.8 min. in WT and 17.4±2.5 min. in Sham; p<0.05). The pancreas of female Akita mice showed a reduced islet count and a decreased mean islet area, which could be reversed by estrogen. Thus estrogen may protect female Akita mice against development of the diabetic phenotype and the parasympathetic dysfunction of the heart. This animal model might be used to investigate gender specific effects of diabetes in the cardiovascular system.Grant Funding Source: NIH
Sex differences in mouse aortic relaxation via estrogen receptor signaling (680.17)
Authors: Ansari Habib , Hamblin Milton 
Published: June 2021

Cardiovascular disease is the leading cause of death both in the United States and worldwide. Estrogen receptors (ERs) have been previously shown to mediate the mechanisms responsible for playing cardioprotective roles. However, the effect of sex on estrogen receptor‐mediated vascular function is not well‐understood. We investigated the effect of the ER‐alpha agonist, PPT on phenylephrine (Phe; 10‐6 M)‐precontracted male and female mouse aortic rings in the presence and absence of the ER‐alpha antagonist, MPP, ERK1/2 inhibitor, PD98059, and +K‐ATP channel blocker, glibenclamide. We found that PPT induced aortic relaxation in both male and female endothelial‐intact mouse aortic rings at concentrations of 100 μM (62% ± 4 for males vs. 86.6% ± 5 for females) and 1000 μM (70% ± 6 for males vs. 99.9% ± 6 for females), respectively. However, in endothelium‐denuded mouse aortas, PPT‐induced relaxation was attenuated in both males and females, and there were no sex differences. MPP obviated PPT‐induced aortic relaxation (100 μM) in endothelial‐intact mouse aortas. Further, attenuated PPT‐induced aortic relaxation was observed when treated with PD98059 or glibenclamide in endothelial‐intact male and female aortas. In summary, we present potential sex differences in estrogen receptor‐mediated mechanisms for aortic relaxation involving ERK1/2 and the +K‐ATP channel.Grant Funding Source: 5K12HD043451
The effect of experimental preeclampsia on cerebral blood flow autoregulation and cerebrovascular function (680.22)
Authors: Johnson Abbie , Chan Siu‐Lung , Moseley Janae , LaMarca Babbette , Cipolla Marilyn 
Published: June 2021

This study investigated changes in CBFAR and vascular function in SD rats that were normal pregnant (NP; d20) or with experimental preeclampsia (ePE; d20). ePE was induced by combining placental ischemia and a high cholesterol diet. CBFAR was determined in vivo during acute infusion of phenylephrine to raise blood pressure and measurement of CBF using laser Doppler. The slope (m) of the pressure vs. CBF curves were compared between ePE (n=9) and NP (n=6). Myogenic responses were determined in isolated and pressurized posterior cerebral arteries (PCA; n=5/gr). mRNA expression of iNOS was determined using qPCR (n=5/gr). ePE caused hypertension (123 ± 4 vs. 111± 2 mmHg, p<0.05) and a 25% increase in plasma 8‐isoprostane (p<0.01 vs. NP), indicating oxidative stress. CBFAR was intact in 7/9 ePE rats and not different from NP rats (m=0.54±0.06 vs. 0.45±0.04; p>0.05). However, 2/9 ePE rats had impaired CBFAR (m=0.93±0.05; p<0.05 vs. NP). PCA from NP rats displayed myogenic activity and were smaller than passive diameters at 150 mmHg (149±17 vs. 210±13 μm; p<0.05). In contrast, the myogenic response was absent in PCA from ePE rats with no difference between active and passive diameters. mRNA expression of iNOS increased 2‐fold in PCA from ePE rats (p<0.01 vs. NP). Thus, CBFAR appears to be intact in the majority of ePE rats. The lack of a myogenic response in PCA from ePE animals may be due to oxidative stress and vascular inflammation.Grant Funding Source: Supported by RO1 NS045940
Influence of age and ischemia on cardiac subsarcolemmal and interfibrillar mitochondria in a novel model of estrogen deficiency (680.6)
Authors: Garvin Alexandra , Aurigemma Nicole , Lehtihet Nadia , Hackenberger Jenna , Korzick Donna 
Published: June 2021

Altered mitochondrial respiration (MR) and calcium retention capacity (CRC) are proposed cardiac cell death mechanisms exacerbated by aging in males. The present study aimed, for the first time, to determine changes in mitochondrial subpopulation function with age and ischemia/reperfusion (I/R) injury in the female heart. A novel model to recapitulate human menopause/age interactions was used in F344 female rats ovariectomized (OVX) at 15mo and studied at 24mo (n=15), vs adult (6mo; n=18). MR and CRC were assessed in isolated subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria following in vivo coronary artery ligation (CAL; 31 min I and 10 min R) or sham. State 3 MR energized by either complex I (CI) or complex II (CII) substrates was selectively reduced by age in SSM (p<0.02), and by I/R in IFM (p<0.05). CRC was less in aged vs. adult IFM with I/R (38%), suggesting earlier mitochondrial permeability transition pore (MPTP) opening. At CI, but not CII, cyclosporine A (CsA) enhanced CRC in adult vs. aged (48%), suggesting reduced protective efficacy with age and MPTP involvement. In contrast to males, our data suggest a sex‐specific phenotype whereby reductions in both SSM and IFM dynamics may play an additive role in the enhanced susceptibility to I/R injury and myocardial infarction in the aged female heart, which remains the leading cause of death in older women.Grant Funding Source: Supported by HL091097, AG044132.
Sex differences in the relationship between cerebral vascular resistance and sympathetic nerve activity: a magnetic resonance imaging study (680.9)
Authors: Hart Emma , Coope Tom , Warnert Esther , Harris Ashley , Stewart Lesley , Nightingale Angus , Wise Richard , Paton Julian 
Published: June 2021

In men, we have found that cerebral vascular resistance (CVR) in the internal carotid (ICA), vertebral (VA) and basilar arteries (BA) is related to muscle sympathetic nerve activity (MSNA). Since sex hormones play a role in blood flow/pressure regulation, we hypothesised that CVR and blood flow in the ICA, VA, and BA would not be related to the level of MSNA or blood pressure (BP) in young women. In normotensive men (n= 11, age; 30 ± 2 yrs) and pre‐menopausal women (n=7; 33±2 yrs) blood flow in the ICA, VA and BA was measured using magnetic resonance phase contrast imaging at 2 locations (1 cm below/above the VA convergence) with concurrent brachial BP measurements. CVR was calculated as mean BP/blood flow. MSNA was similar in men and women (30 ± 1 vs. 28±1 bursts/100 hb) and positively related to CVR in the left and right ICA (r=0.74, r=0.62, P0.05). Interestingly, mean BP was negatively correlated with blood flow in the ICA, VA and BA in men (r=‐0.54, r=‐0.56, r=‐0.50, P<0.05), but not in women (P<0.05). In summary, men with high CVR and low blood flow in the intracranial arteries had higher MSNA and BP. Cerebral blood flow and CVR may be important in setting resting BP and MSNA in men but not in pre‐menopausal women. British Heart Foundation funded.Grant Funding Source: Supported by the British Heart Foundation
Aqueous extract of Acanthopanax divaricatus var. chiisanensis ameliorates blood pressure through a nitric oxide‐dependent mechanism: in vivo and in vitro studies (681.10)
Authors: Park Soo‐yeon , Do Gyeong‐Min , Shin Jae Ho , Kwon Oran 
Published: June 2021

High blood pressure is one of the most important modifiable risk factors for cardiovascular disease. Many emerging evidence indicate that an array of plants might have a potential to regulate blood pressure by various mechanisms. In this study, we investigated the antihypertensive effects of Acanthopanax divaricatus var. chiisanensis (AE) and its active compound, Acanthoside‐D (AD), and also their underlying mechanisms on vascular actions in vivo and in vitro. Spontaneously hypertensive rats (n=10/group) were fed high‐cholesterol diet with AE or AD by gavage for 14 weeks, and their blood pressure was recorded weekly. Blood pressure was significantly reduced in the AE group compared to the control group. Consistent with this, we observed a significant reduction in arterial wall thickness by H&E staining and an activation of endothelial nitric oxide synthase by immuno‐fluorescence staining in the AE group. The findings in vivo were confirmed by increase of nitric oxide production and activation of PI3‐kinase‐Akt‐eNOS pathway in human umbilical vein endothelial cells after AE treatment. Taken together, the results provide a basis for the use of AE in regulating blood pressure by enhancing endothelial function in a nitric oxide‐dependent mechanism.Grant Funding Source: Supported by MAF/FST Projects (S111111L010000) and MEST/Brain Korea 21 PLUS (22A20130012143).
Blockade of transient receptor vanilloid channels prevents the sympathoexcitatory response to central NaCl infusion (683.3)
Authors: Simmonds Sarah , Stocker Sean 
Published: June 2021

Increased cerebrospinal fluid sodium concentration elevates sympathetic nerve activity (SNA) and arterial blood pressure (ABP) in salt‐sensitive hypertension. Recent in vitro evidence suggests the brain senses changes in osmotic pressure through TRPV1 channels. The present study investigated whether the sympathoexcitatory response to increased cerebrospinal fluid NaCl was mediated by central TRPV1 channels. Male Sprague‐Dawley rats were anesthetized with Inactin and instrumented with a lateral intracerebroventricular (ICV) cannula. ICV infusion of 1M NaCl (n=8) significantly increased lumbar SNA (140±12%), heart rate (20±7bpm), and mean ABP (9±1mmHg). ICV pretreatment with the broad‐spectrum TRPV channel blocker ruthenium red (5mM, 2uL, n=8) eliminated the sympathoexcitatory response to ICV 1M NaCl: lumbar SNA (106±5%), heart rate (‐6±7bpm), and mean ABP (1±2mmHg). Similarly, ICV pretreatment with the selective TRPV1 channel antagonist SB366791 (3mM, 2uL, n=4) prevented any change in lumbar SNA (106±3%), heart rate (4±6), and mean ABP (1±1mmHg). ICV injection of ruthenium red or SB366791 did not alter any variable. These findings suggest that central TRPV1 channels mediate the sympathoexcitatory response to acute increases in cerebrospinal fluid NaCl concentration.Grant Funding Source: Supported by NIH R01HL113270 and AHA Established Investigator Award
Focal hemorrhagic stroke in the left or right rat posterior insular cortex results in equipotent changes in sympathetic activity (686.11)
Authors: Marins Fernanda , D’Abreu Bárbara , Limborço‐Filho Marcelo , Fontes Marco Antonio 
Published: June 2021

Evidence suggests that unilateral damage to the insular cortex(IC) leads to autonomic imbalance and cardiovascular (CV) dysfunction. We evaluated the CV effects from focal hemorrhage (ICH) into the left (L) or right (R) IC. Wistar rats were anesthetized for microinjection of autologous arterial blood (ICH) or saline (200nL, n=10 each side/group) into the L or R IC (0mm AP/ ±5.8mm LL/ 7mm DV). After 24 hours, mean arterial pressure (MAP) and heart rate (HR) were measured in awake condition. Then, ICH and control group (n=7 each side) were anesthetized and renal sympathetic activity (RSNA) was record. ICH increased baseline HR (Δ:L‐ICH 471±8 vs saline 407±7bpm; R‐ICH 465±8 vs saline 408±5bpm, P<0.05) without changing MAP. HR was restored to baseline levels after i.v. atenolol injection (2mg/kg). Strikingly, ICH rats presented a reduced baseline RSNA (Δ:L‐ICH 112±5 vs saline 148±7spikes/sec; R‐ICH 121±4 vs saline 149±10spikes/sec, P<0.05). There were no differences between L‐ and R‐ICH. We conclude that focal stroke into posterior IC can alter the cardiac and renal autonomic control without lateral predominance. These findings can help to understand the cardiac and renal dysfunctions observed after cortical damage.Grant Funding Source: CNPq, Fapemig, Capes and INCT NanoBioFar
Repetitive electroacupuncture attenuates cold‐induced hypertension is associated with opioid precursors in hypothalamic paraventricular and arcuate nuclei (686.2)
Authors: Li Min , Tjen‐A‐Looi Stephanie , Longhurst John 
Published: June 2021

Acupuncture lowers elevated blood pressure in clinical and experimental hypertension, possibly through an opioid mechanism. To mimic human studies, we performed repeated electroacupuncture (EA) on unanesthetized male SD rats exposed to cold (5°C) for 11 weeks. Systolic blood pressures (SBP) were measured weekly. Rats were randomly divided into EA (n=9), sham (n=6) and untreated hypertension groups (n=6) after 6 weeks of cold exposure when elevated SBP had stabilized. EA and sham groups then received either repetitive EA (1‐4 mA, 2 Hz, 0.5 ms) at ST36‐37 acupoints bilaterally (overlying deep peroneal nerve) or sham (needle placement without electrical stimulation) 30 min twice weekly for 5 weeks. The elevated SBP in the EA group was reduced after 6 sessions and remained low throughout treatment (139 ± 3 vs. 175 ± 3 mmHg, EA vs. sham) and 72 hr after termination of EA (155 ± 4 vs. 187 ± 3 mmHg, after EA vs. sham). Both preproenkephalin (PPE) and proopiomelanocortin (POMC) mRNA in PVN 72 hr after EA were increased in the EA (0.43±0.001 and 85±1.2, respectively) compared to the sham group (0.30±0.001 and 44±1.1) and the untreated hypertensive rats (0.31±0.012 and 42±1.2). POMC mRNA also was increased in the arcuate nucleus of the EA group (100± 3.2 vs. 82± 3.8, EA vs. sham). Thus, prolonged inhibition of elevated blood pressure by action of EA is associated with prolonged increases of opioid mRNA expression in the PVN and ARC.Grant Funding Source: Supported by NIH HL‐63313 and HL‐072125