bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antihypertensive therapy reduces myogenic tone and increases the resting diameter of cerebral penetrating arterioles in hypertensive rats (1070.3)
Authors: Pires Paulo , Jackson William , Dorrance Anne 
Published: June 2021

Hypertension impairs neurovascular coupling, possibly by altering the structure and function of cerebral penetrating arterioles (PenA). We hypothesized that an antihypertensive therapy (AhT) would reduce myogenic tone and increase the lumen diameter of PenA in stroke‐prone spontaneously hypertensive rats (SHRSP). Twelve‐week‐old male SHRSP received hydralazine (150mg/L)+hydrochlorothiazide (50mg/L)+reserpine (4mg/L) in the drinking water for 6 weeks (SHRSP+AhT). Controls received regular drinking water (SHRSP). PenA function and structure were studied by pressure myography. Data are shown as means±SEM, SHRSP vs SHRSP+AhT, n=8 for each group. AhT significantly reduced blood pressure (systolic blood pressure: 214±4 vs 130±6, p<0.05). AhT reduced PenA myogenic tone (%tone: 47.9±4.4 vs 29.1±3.3, p<0.05), and increased PenA resting diameter (34.6±1.9 vs 43.8±4.5 μm, p<0.05). PenA from SHRSP+AhT dilated less to 0.1 μM nifedipine (change in diameter from resting: 24.3±2.5 vs 12.5±1.8 μm, p<0.05). AhT did not increase PenA passive lumen diameter (63.7±3.3 vs 60.2±3.7 μm), but reduced wall thickness (11.7±1.0 vs 9.2±0.8 μm, p<0.05). These data support our hypothesis and indicate that AhT may improve local perfusion and prevent the consequences of hypertension on the cerebral microcirculation.Grant Funding Source: Supported by AHA (12PRE8960019:PWP, 13GRNT17210000:AMD) and NIH (P01‐HL07687)
Mild deoxycorticosterone (DOCA)/salt‐induced hypertension causes cerebral microvascular dysfunction via a rho kinase dependent mechanism (1070.4)
Authors: De Silva T. Michael , Lynch Cynthia , Grobe Justin , Faraci Frank 
Published: June 2021

Hypertension is a major cause of cerebrovascular disease. Microvascular dysfunction in brain is a key feature of small vessel disease that increases the risk of stroke and cognitive impairment. We tested whether mild DOCA/salt‐induced hypertension alters cerebral microvascular function. We treated male C57Bl6 mice with DOCA and 0.9% salt in their drinking water for 3 weeks and measured microvascular reactivity in anesthetized mice using a cranial window preparation. Blood pressure was elevated after DOCA/salt treatment (79±2 vs 95±3 mmHg; P<0.01). Endothelium‐dependent dilation of small cerebral arterioles was selectively impaired in mice treated with DOCA/salt compared with sham (eg, 10 μM acetylcholine: 29±5% vs 11±2%; P<0.01). Endothelium‐independent vasodilation to nitroprusside (an NO donor) or nifedipine (a Ca2+ channel blocker) was similar between groups. Rho kinase is a potential mediator of cerebrovascular disease. Local inhibition of Rho kinase with Y27632 did not affect endothelium‐dependent dilation in sham. In contrast, Y27632 restored endothelium‐dependent dilation to normal in DOCA/salt mice (3 µM) (10 μM acetylcholine: 10±1% vs 22±4%; P<0.01). These findings demonstrate that mild DOCA/salt‐induced hypertension profoundly impacts cerebral microvascular function. Our findings identify Rho kinase as a key contributor to DOCA/salt‐induced endothelial dysfunction in brain.Grant Funding Source: Supported by NIH (HL‐62984, HL‐113863) VA (BX001399), Fondation Leducq and NHMRC (1053786)
Pulse pressure oscillations regulate cerebrovascular reactivity to flow (1070.5)
Authors: Raignault Adeline , Bolduc Virginie , Lesage Frédéric , Thorin Éric 
Published: June 2021

In vivo, arterial blood pressure is oscillatory and pulsated. This pulse pressure (PP) corresponds to the difference between the systolic and diastolic pressure, and its frequency is dictated by heart rate (bpm). Our aim was to determine, in vitro, the unknown impact of PP (30 mm Hg, 550 bpm) on endothelial shear stress sensitivity (flow‐mediated dilatation) of mouse cerebral arteries. Methods/results: We developed an original system that generates a pulse‐wave adjustable in amplitude and frequency, and can be connected to a pressure arteriograph. Middle cerebral arteries (≍160 µm diameter, n=10 per group) were isolated from 3‐month old C57Bl6 mice and pressurized at 60 or 100 mm Hg either in static pressure (SP) or PP conditions. At 60 mm Hg, pre‐constricted arteries similarly dilated to an increase in flow up to a shear stress of 15 dyn/cm2, to 59±6% of the maximal diameter in PP, and 52±10% in SP conditions. In response to a higher shear stress of 20 dyn/cm2, however, arteries further dilated in PP (73±7%; p<0.05) unlike in SP (43±9%) conditions. At 100 mm Hg, arteries dilated in response to low shear stress (8 dyn/cm2) but less at high shear stresses (20 dyn/cm2): dilation was reduced by 50% in SP (from 44±11% to 23±11%; p<0.05) and 75% in PP (from 34±3% to 8±4%; p<0.05) conditions. Conclusion: PP increases the sensitivity of the endothelium to shear stress at physiological pressure (60 mm Hg) while it limits its sensitivity to high shear stress at high pressure (100 mm Hg), suggesting that PP regulates the endothelial function to critically adjust vessel diameter and flow to neuronal metabolic demand.Grant Funding Source: CIHR
Gestational chronic intermittent hypoxia alters glucose homeostasis in rat male offspring (1072.3)
Authors: Iqbal Waseem , Hardy Daniel , Ciriello John 
Published: June 2021

We have shown that exposure to chronic intermittent hypoxia (CIH) during pregnancy results in offspring with increased fat deposition that are hyperglycemic, hyperinsulinemic, and have impaired early‐stage glucose tolerance in adulthood, but the underlying mechanisms are unknown. This study was done to examine changes in the glucoregulatory function of the liver as a result of CIH exposure during gestational development. Female Sprague‐Dawley rats were mated and exposed daily to CIH throughout gestation. Offspring were sacrificed at postnatal day‐1 or 6‐wks of age to determine immediate and long‐term changes in liver function. By 6 wks of age, male CIH offspring had higher plasma corticosterone concomitant with higher liver protein expression of 11β‐hydroxysteroid dehydrogenase type I and glucocorticoid receptor (GR). These were associated with lower liver X receptor (LXR) protein expression. Analysis of GR and LXR‐direct target genes in gluconeogenesis showed that glucose‐6‐phosphatase expression was higher in CIH offspring, while no changes in phosphoenolpyruvate carboxykinase protein levels were observed. Taken together, these data suggest that gestational exposure to CIH results in long‐term alteration of hepatic glucose homeostasis via increased glucocorticoid signaling and decreased regulation of gluconeogenic enzymes by LXR. Supported by HSF of Ontario and CIHR.Grant Funding Source: Heart and Stroke Foundation of Ontario and Canadian Institutes of Health Research
O‐GlcNacase overexpression restores coronary endothelial dysfunction in type 1 diabetic mice (1076.1)
Authors: Dai Anzhi , Donthamsetty Reshma , Han Ying , Scott Brian , Wang Hong , Dillmann Wolfgang , Makino Ayako 
Published: June 2021

Cardiac ischemia is a leading cause of morbidity and mortality in diabetes, and endothelial cell (EC) dysfunction is implicated in coronary arterial disease. O‐linked N‐acetyglucosamine (O‐GlcNAcylation) is a post‐translational modification that is tightly controlled by two enzymes: O‐GlcNAc transferase (OGT, catalyzes the addition of an O‐GlcNAc to proteins) and O‐GlcNAcase (GCA, removes GlcNAc from proteins). In this study, we examine the role of GCA in coronary endothelial dysfunction in type 1 diabetic mice.We generated EC‐specific, inducible GCA transgenic mice and induced diabetes in these mice with streptozotocin. In diabetic mouse coronary endothelial cells (MCECs), GCA expression was significantly decreased and protein O‐GlcNAcylation was increased. GCA overexpression in diabetic mice decreased O‐GlcNAcylation in MCECs. Capillary density in the left ventricle was decreased in diabetes, while GCA overexpression significantly increased the density to the control level. Endothelium‐dependent relaxation was attenuated in diabetic coronary arteries (CAs) and restored by GCA overexpression. These data suggest that elevated protein O‐GlcNAcylation due to decreased GCA protein expression in MCECs contributes to coronary endothelial dysfunction in diabetes, whereas overexpression of GCA in ECs improves endothelial function and may have a beneficial effect on coronary vascular complications in diabetes.Grant Funding Source: supported by NIH/NHLBI(HL115578)
Expression and function of BK and Kv1.5 channels in aortic smooth muscle from lean and obese Zucker rats (1077.5)
Authors: Rottgen Trey , Fancher Ibra , Dick Gregory 
Published: June 2021

We tested the hypothesis that metabolic syndrome is associated with reduced expression and function of K+ channels in smooth muscle. Aortic smooth muscle from male lean and obese Zucker rats was used as a model. Whole‐cell patch clamp experiments indicated that Ca2+‐activated (BK) and voltage‐dependent (KV) K+ currents dominated membrane conductance. Penitrem A (1 uM) and DPO‐1 (10 uM), selective antagonists of BK and KV1.5 channels were used to determine the expression of these channels. In lean rats, penitrem A inhibited 37 ± 6% of current at +100 mV, whereas subsequent addition of DPO‐1 inhibited 74 ± 4% of the remaining current. In obese rats, penitrem A inhibited 19 ± 6% of current at +100 mV, whereas subsequent addition of DPO‐1 inhibited 78 ± 3% of the remaining current. The penitrem A‐sensitive BK current was 2.7 ± 0.7 fold greater in lean rats. In contrast, and surprisingly, the DPO‐1‐sensitive KV1.5 current was 1.5 ± 0.2 fold greater in obese rats. Western blots supported the patch clamp studies, as BK channel protein was 1.4 ± 0.1 fold greater in lean rats, while KV1.5 protein was 2.5 ± 0.4 fold greater in obese rats. These data indicate that metabolic syndrome decreases the expression of BK channels, but simultaneously increases KV1.5 channel expression. We suggest this opposite change in K+ channel expression may represent a compensatory stage of metabolic disease that serves to preserve cardiovascular function.Grant Funding Source: Supported by T32HL090610
High‐density lipoprotein modulates glucose metabolism in cardiomyocytes (1078.12)
Authors: Siebel Andrew , Heywood Sarah , Henstridge Darren , Carey Andrew , Delbridge Lea , Kingwell Bronwyn 
Published: June 2021

The effects of HDL on the coronary vasculature are well understood, however its direct actions on the myocardium remain to be elucidated. We have previously shown that HDL stimulates glucose uptake into skeletal muscle, but whether HDL‐mediated glucoregulatory mechanisms exist within cardiac muscle is unknown. We sought to determine the effect of HDL on myocardial glucose uptake, glycolysis, glucose oxidation, oxidative metabolism and the associated intracellular signalling mechanisms using a neonatal rat ventricular cardiomyocyte model. HDL (50µg/ml) treatment increased glucose uptake by 47±10% and glycolysis by 43±8% in association with rapid activation of Akt/PKB and its downstream target AS160, a regulator of GLUT4 translocation. HDL also increased basal and maximal mitochondrial respiration by 40±8% and ATP turnover by 48±8%. Glucose oxidation was increased by 30±6% with 50µg/ml HDL and may contribute to observed increases in total mitochondrial respiration. HDL‐mediated increases in both glycolytic and mitochondrial respiratory capacity may limit ATP depletion during ischaemia‐reperfusion and thereby minimise myocardial cell damage.Grant Funding Source: Supported by the National Heart Foundation of Australia, National Health & Medical Research Council
Coronary arterial wave form relates to compression of intramural vasculature controlled by left ventricular end diastolic pressure (1079.11)
Authors: Spaan Jos , Rolandi Cristina , Wiegerinck Esther , Piek Jan , Baan Jan , Siebes Maria 
Published: June 2021

The aim of this study was to test the hypothesis that left ventricular, LV, end diastolic pressure, LVEDP, contributes to coronary arterial flow waveform since it reflects venous pressure determining microvascular intramural blood volume, MIBV.In 12 patients undergoing coronary catheterization, coronary flow velocity and pressure were measured simultaneously in undiseased vessels with a 0.014‐in dual‐sensor guidewire and LV pressure with an open ended catheter. Measurements were performed under intact autoregulation. The signals were analyzed with wave intensity analysis that allows separating the contribution to the net coronary energy coming from the aorta and from the microcirculation.Both the microcirculatory‐originating waves, generated during contraction (backward compression wave, BCW) and relaxation (backward expansion wave, BEW), were linearly related to LVEDP (p<0.04 for both waves) while both the aortic‐generating waves during contraction and relaxation were not.It is known that LVEDP relates well to coronary venous pressure hence, an increase in LVEDP reduces the pressure head over the microcirculation. Its effect on flow can be compensated by autoregulation but also by increasing MIBV due to increasing microvascular pressure pressure. Increased MIBV results in an enhanced BCW by the elastance effect when the myocardium is contracting and consequently it results also in a higher BEW because of restoration forces due to compliance of the microcirculation. By increasing the energy of the BCW and BEW, LVEDP has an influence on the coronary flow waveform.
Peroxynitrite disrupts endothelial caveolae leading to eNOS uncoupling and diminished flow‐mediated dilation in coronary arterioles of diabetic patients (1082.3)
Authors: Bagi Zsolt , Feher Attila , Cassuto James 
Published: June 2021

Peroxynitrite (ONOO‐) contributes to coronary microvascular dysfunction in diabetes (DM). We hypothesized that in DM ONOO‐ interferes with the function of coronary endothelial caveolae, which plays an important role in nitric‐oxide (NO)‐dependent vasomotor regulation. Flow‐mediated dilation (FMD) of coronary arterioles was investigated in DM (n=41) and nonDM (n=39) patients undergoing heart surgery. NO‐mediated coronary FMD was significantly reduced in DM patients, which was restored by ONOO‐ scavenger, uric‐acid, whereas exogenous ONOO‐ reduced FMD in nonDM subjects. Immuno‐electronmicroscopy demonstrated an increased 3‐nitrotyrosine formation (ONOO‐ specific protein nitration) in endothelial plasma membrane in DM, which co‐localized with caveolin‐1 (Cav‐1), the key structural protein of caveolae. The membrane‐localized Cav‐1 was significantly reduced in DM and also in high glucose‐exposed coronary endothelial cells. We also found that DM patients exhibited a decreased number of endothelial caveolae, whereas exogenous ONOO‐ reduced caveolae number. Correspondingly, pharmacological (methyl‐β‐cyclodextrin) or genetic disruption of caveolae (Cav‐1‐knockout mice) abolished coronary FMD, which was rescued by sepiapterin, the stable precursor of NO synthase cofactor, tetrahydrobiopterin. Sepiapterin also restored coronary FMD in DM. Thus, we propose that ONOO‐ selectively targets and disrupts endothelial caveolae, which leads to NO synthase uncoupling, hence reduced NO‐mediated coronary vasodilation in DM patients.Grant Funding Source: Supported by NIH HL104126
Thermal stress conditions endothelial cells and improves cellular function (1084.10)
Authors: Needham Karen , Macrorie Sarah , Minson Christopher , Gilbert Jeffrey 
Published: June 2021

It is well established that temporary exposure to a stressor, such as heat, can induce the production of proteins that confer cellular protection (heat shock proteins ‐ HSP). Our lab has shown that exercise training (a stressor) in pregnant rats increases production of HSP 27, 60, and 90 in the placenta. The aim of this study is to determine whether heat shock, resulting in the up‐regulation of HSPs, improves endothelial function in human umbilical vascular endothelium (HUVEC) treated with normal pregnant rat serum or serum from rats with placental ischemia induced hypertension (RUPP). HUVECs were heat shocked at 42.5° C for 4hrs followed by 2hr recovery at 37° C. Extracts from shocked cells had 4x HSP 70 (p<0.01) and 3x HSP 27 (p<0.01) protein levels over the control. Shocked cells and 37° C control cells were treated with NP or RUPP serum and function was assessed with angiogenesis and wound healing assays. Tubule length counts in heat treated cells were at three times the level of no shock controls (p <0.01), without any effect from serum. In the wound assay RUPP/heat shocked cells tended toward greater mitogenesis and motility. These benefits may involve endothelin 1, which has been shown to promote HUVEC proliferation and migration and was elevated by 20% (p<0.05) in the media of RUPP/heat shock HUVECS in our study. These results suggest that human endothelial cells may improve function with conditioning by low level stressors. Such conditioning, as would be conferred by exercise, may improve the outcome for women with preeclampsia.Grant Funding Source: Supported by NIH RO1HL114096 and AHA 10SDG2600040
Exercise before and during pregnancy does not lower blood pressure in an sFlt‐1 infusion model of preeclampsia in the rat (1084.9)
Authors: Banek Christopher , Gillham Haley , Needham Karen , Johnson Sarah , Beasley Kara , Gilbert Jeffrey 
Published: June 2021

Preeclampsia (PE) is a pervasive, pregnancy‐specific syndrome defined by new onset hypertension and proteinuria. Additionally, PE is often associated with increased soluble VEGF Receptor‐1 (sFlt‐1), decreasing the bioavailability of vascular endothelial growth factor (VEGF) creating angiogenic imbalance leading endothelial dysfunction and hypertension. We recently reported exercise training attenuates placental ischemia‐induced hypertension and restores angiogenic balance but the mechanism remains unclear. Thus, we hypothesized exercise training before and during (EBD) pregnancy would increase plasma free VEGF and lower blood pressure in an sFlt‐1 infusion model of PE. EBD rats voluntarily exercised for six weeks before and during pregnancy on an activity wheel. Age‐matched sedentary (Sed) controls were housed without wheel access. After breeding, the dams regained access to the activity wheels. Osmotic minipumps infused sFlt‐1 (500ng/hr) or vehicle from gestational day 14 to day 19 when blood pressures and tissues were collected. In both Sed and EBD groups, sFlt‐1 infusion increased (p<0.05) blood pressure, decreased (p<0.05) endothelial dependent vascular relaxation of mesenteric vessels via wire myography to acetylcholine (ACh) and decreased (p<0.05) endothelial tube formation by HUVECs on Matrigel. EBD had no effect on sFlt‐1 hypertension but improved (p<0.05) vascular endothelial relaxation to ACh and improved (p<0.05) HUVEC tubule formation. In contrast with our hypothesis, these data suggest sFlt‐1‐induced hypertension in pregnancy is not remediated by EBD despite improved tubule formation in vitro and vascular endothelial function ex vivo. Together these data suggest improvements in vascular endothelial function as a result of exercise before and during pregnancy may be due to the stimulation of alternative pro‐angiogenic and vasorelaxant pathways. Further studies are underway to elucidate these alternative mechanisms.Grant Funding Source: Supported by NIH RO1HL114096 and AHA 10SDG2600040
High fat feeding induces exaggerated endothelial dysfunction and insulin resistance in rats exposed to maternal separation (1085.7)
Authors: Loria Analia , Fox Brandon , Pollock David , Pollock Jennifer 
Published: June 2021

We previously reported that adult male rats exposed to MatSep (3 hrs/day from day 2 to 14 of life) display normal baseline cardiovascular parameters but enhanced responses to angiotensin II (AngII) compared to controls (C, non‐MatSep littermates). We tested the hypothesis that a chronic HF diet (60% fat cal., 0.4 salt; 6 months) exaggerates metabolic and/or cardiovascular indices in MatSep rats. Plasma fasting glucose and insulin were higher in MatSep vs. C rats (p<0.05), showing a greater HOMA index in MatSep than C rats (1.0±0.1 vs. 1.7±0.1, p<0.05). Plasma adiponectin was lower in MatSep vs. C rats (19±2 vs. 28±2 ug/ml, p<0.05), although body weight and leptin were similar between groups. No differences in mean arterial pressure or heart rate were observed between MatSep and C rats (105±2 vs. 102±2mmHg; 326±6 vs. 317±3 bpm; n=6). Wire myography of thoracic aortae showed a greater vasoconstrictive response (%max constriction) to AngII (17±2 vs. 6±1, p<0.05) and phenylephrine (59±4 vs. 29±5, p<0.05) from MatSep rats. L‐NAME pre‐incubation revealed a loss of NO buffering capacity to AngII in MatSep aortae only (p<0.05). Impaired acetylcholine‐induced relaxation was greater in aortae from MatSep rats (49±6 vs. 27±3 % relax, p<0.05). These data reveal that MatSep followed by HF feeding induces a synergistic effect on disrupting vascular function and glucose homeostasis increasing the risk to cardiovascular disease.Grant Funding Source: HL111354 and PO1 HL69999
Vascular dysfunction, arterial hypertension and insulin‐resistance in offspring of a mouse model of preeclampsia: prevention by sildenafil (1085.8)
Authors: Cerny David , Rexhaj Emrush , Bouillet Elisa , Soria Rodrigo , Sartori Claudio , Allemann Yves , Rimoldi Stefano , Scherrer Urs 
Published: June 2021

In humans, offspring of mothers with preeclampsia display generalized vascular dysfunction and premature cardiovascular morbidity, but underpinning mechanisms and possibilities for prevention are unknown. In mice, offspring of restrictive diet pregnancy (RDP), a model mimicking preeclampsia in humans, display insulin resistance and vascular dysfunction offering an opportunity to study interventions aimed at preventing these problems. Sildenafil administration to preeclamptic rats increases birth weight in the offspring.We assessed vascular function in vitro (mesenteric artery dilation), arterial blood pressure (carotid artery) and insulin sensitivity (clamp studies) in vivo in offspring of RDP (Sildenafil 40 mg/kg/day or vehicle in drinking water, day 7 to end of pregnancy) and control mice. As expected, offspring of RDP displayed impaired acetylcholine‐induced mesenteric artery dilation (P<.0001 vs. ctrl), arterial hypertension (119±7 vs. 112±5 mmHg, X±SD, P=.04 vs. ctrl) and insulin resistance (Glucose Infusion Rate 77.4±10.7 vs. 96.7±12.2 mg/kg*min, P<.001 vs. ctrl). Sildenafil administration during RDP prevented these problems in the offspring (all P>.5 vs. ctrl). We show for the first time that in mice sildenafil administration during RDP prevents arterial hypertension and insulin resistance in the offspring. We speculate that in humans sildenafil has similar beneficial effects.