bluuebunny/crossref_metadata_2025_split huggingface dataset:
Activators of endothelial calcium‐activated potassium channels enhance the availability of NO released in response to shear stress (1079.22)
Authors: Lunn Stephanie , Govindasamy Natasha , Zwozdesky Myron , Wei Ran , Liew Amanda , Kerr Paul , Plane Frances 
Published: June 2021

Nerve‐evoked vasoconstriction of resistance arteries is limited by shear stress‐induced release of endothelium‐derived nitric oxide (NO) and activation of endothelial Ca2+‐activated potassium (KCa) channels. NO and KCa are often regarded as separate pathways for modulation of vascular tone but recent data from our lab indicate small molecule activators of endothelial KCa channels enhance the availability of NO released in response to agonists. In this study we have extended these observations to test the hypothesis that activators of KCa channels can enhance the availability of NO released in response to increases in shear stress caused by nerve‐evoked vasoconstriction.In the rat perfused mesenteric bed, N‐cyclohexyl‐N‐[2‐(3,5‐dimethyl‐pyrazol‐1‐yl)‐6‐methyl‐4‐pyrimid‐iamine (CyPPA; 1‐10 μM), a small molecule activator of small conductance KCa channels (SKCa) did not alter basal perfusion pressure but did cause endothelium‐ and concentration‐dependent attenuation of nerve‐evoked vasoconstriction. Inhibitors of NO synthase, soluble guanylyl cyclase or SKCa channels, significantly enhanced nerve‐mediated vasoconstriction and prevented the effects CyPPA. In contrast, scavengers of superoxide enhanced the ability of CyPPA to limit vasoconstriction. Inhibition of endothelial intermediate conductance KCa channels or cyclooxygenase did not alter nerve‐evoked responses and did not alter the effects of CyPPA whereas Our findings indicate SKCa channel openers can enhance NO‐mediated modulation of nerve‐evoked vasoconstriction without altering basal perfusion. This finding is significant as in vivo such an effect could reduce vasoconstriction whilst avoiding the baroreceptor activation seen with direct vasodilators and thus may reduce blood pressure whilst maintaining the physiological coupling between nerves, endothelium and changes in blood flow.Supported by HSFC. SL is supported by a QEII award from the University of Alberta.
Local metabolic and feed forward regulation of coronary blood flow (1079.23)
Authors: Pradhan Ranjan , Beard Daniel , Gorman Mark , Feigl Eric 
Published: June 2021

When red blood cells reach a low oxygen environment they release a small amount of ATP into the plasma. The ATP and its breakdown products ADP and AMP act on capillary endothelial purinergic receptors to initiate a vasodilator response that is conducted upstream. This forms the basis of a local metabolic feedback control mechanism where the red blood cell is the sensor of the balance of oxygen delivery (flow) versus oxygen consumption by the heart. This is a paradigm shift from the previous idea that the myocardium acts as the sensor of oxygen balance. The existence of feed forward control of the coronary circulation by sympathetic beta adrenoceptor vasodilation, and a modest alpha adrenoceptor vasoconstriction adds complexity and redundancy. A mathematical computer model has been developed to understand the simultaneous action of feedback and feed forward control of coronary blood flow. Data from canine experiments during control exercise and with adrenergic and purinergic receptor blockade were analyzed to elucidate the simultaneous interplay between local metabolic feedback control, and feed forward coronary control. The results indicate that ~71% of coronary vasodilation is due to purinergic local metabolic control and ~27% is due to feed forward adrenergic control during exercise.Grant Funding Source: NIH U01 HL 118738
Dysregulation of pressure‐induced Ca2+ signaling and myogenic constriction of cerebral arteries in aged hypertensive mice (1079.3)
Authors: Toth Peter , Csiszar Anna , Tucsek Zsuzsanna , Sosnowska Danuta , Gautam Tripti , Koller Akos , Schwartzman Michal , Sonntag William , Ungvari Zoltan 
Published: June 2021

Hypertension in the elderly substantially increases the risk of stroke and vascular cognitive impairment (VCI) in part due to an impaired functional adaptation of aged cerebral arteries to high blood pressure. To elucidate the mechanisms underlying impaired autoregulatory protection in aging, hypertension was induced in young (3 mo) and aged (24 mo) C57/BL6 mice by chronic infusion of angiotensin II and pressure‐induced changes in smooth muscle (SMC) [Ca2+]i and myogenic constriction of middle cerebral arteries (MCA) were assessed. In MCAs from young hypertensive mice pressure‐induced increases in VSMC [Ca2+]i and myogenic tone were increased and these adaptive responses were inhibited by the cytochrome P450 ω‐hydroxylase inhibitor HET0016 and the TRP channel blocker SKF96365. Administration of 20‐HETE increased SMC [Ca2+]i and constricted MCAs and these responses were inhibited by SKF96365. MCAs from aged hypertensive mice did not show adaptive increases in pressure‐induced calcium signal and myogenic tone and responses to HET0016 and SKF96365 were blunted. Inhibition of BK channels by iberiotoxin enhanced SMC [Ca2+]i and myogenic constriction in MCAs of young normotensive animals, whereas it was without effect in MCAs of young hypertensive mice. Iberiotoxin did not restore myogenic adaptation in MCAs of aged hypertensive mice. Thus, functional maladaptation of aged cerebral arteries to hypertension is due to the dysregulation of pressure‐induced, 20‐HETE and TRP channel‐mediated SMC calcium signaling, whereas overactivation of BK channels is unlikely to play a role in this phenomenon.Grant Funding Source: Supported by the American Heart Association and the Nemzeti Fejlesztési Ügynökség
Aging exacerbates hypertension‐induced intracerebral microbleeds in mice (1079.6)
Authors: Tarantini Stefano , Toth Peter , Sosnowska Danuta , Gautam Tripti , Tucsek Zsuzsanna , Koller Akos , Sonntag William , Csiszar Anna , Ungvari Zoltan 
Published: June 2021

Aging is associated with high prevalence of cerebral microbleeds (CMBs) in the elderly, which contribute to the age‐related decline in higher cortical function. Despite its clinical significance, the pathophysiology of CMBs is poorly understood. To establish a novel model of CMB hypertension was induced in young (3 mo) and aged (24 mo) C57B/6 mice (s.c AngII, p.o. L‐NAME). Neurological examination and gait analysis followed by histological analysis of CMBs in serial sections of the brain showed that in the aged mice the same level of hypertension lead to significantly earlier onset and increased incidence of CMBs (incidence: young:27%, aged:90% of the animals; average number of CMBs: young:15±3, aged:28±2). Aging exacerbated hypertension‐induced cerebral oxidative stress, NADPH oxidase expression (Nox2 mRNA: 2±0.1 fold increase in aged vs. young) and activation of MMPs (6±0.9 fold increase in aged vs. young). Treatment of aged mice with the dietary polyphenol resveratrol (200 mg/kg for 20 days) significantly attenuated oxidative stress, down‐regulated NADPH oxidase, decreased MMP activity and prevented/delayed the development of CMBs. Collectively, aging exacerbates hypertension‐induced intracerebral microbleeds in mice likely by increasing oxidative stress and MMP activation. Therapeutic strategies to reduce microvascular oxidative stress and MMP activity should be considered for the prevention of CMBs in the elderly.Grant Funding Source: Supported by the Oklahoma Center for the Advancement of Science and Technology
The R403Q mutation alters isometric and energetic properties in 2 month mice (1081.1)
Authors: Birch Camille , Konhilas John 
Published: June 2021

Familial hypertrophic cardiomyopathy is a primary disease of the sarcomere. The R403Q mutation resides at the actin‐interaction site on myosin and leads to progressive hypertrophic cardiomyopathy that can lead to sudden cardiac death or congestive heart failure. We hypothesized that the R403Q mutation intrinsically increases the energetic cost of contraction.To do this, we assessed Ca2+‐sensitivity of tension and cross‐bridge kinetics in de‐membranated cardiac trabeculae from wild‐type (WT) and R403Q hearts at 2 months of age. We measured cross‐bridge kinetics using 2 methods: (1) the rate of ATP hydrolysis (off‐rate) by NADH oxidation, and (2) the rate of force redevelopment (ktr) by a rapid release‐restretch protocol.Male R403Q mice display a decrease in Ca2+ sensitivity compared to WT males and females at SL 2.0μm. R403Q males display increased tension cost at SL 2.0μm when compared to WT counterparts. At maximal activation, the rate of force redevelopment is not significantly different between R403Q and WT males. Myosin heavy chain isoform gel analysis reveals no difference in β‐myosin content between R403Q mice and WT controls.Although maximal ktr is not significantly different between WT and R403Q males, an increase in ATP hydrolysis suggests an alteration in binding kinetics. Along with no overt pathology at 2 months, the R403Q mutation alters the energetic cost of contraction and isometric properties.Grant Funding Source: Supported by R01 HL098256A and T32HL007955
The influence of estrogen on circadian rhythms of heart rates and cardiac sympathetic nerve in female rats (1083.6)
Authors: Marui Shuri , Matsuda Mayumi , Sato Nobuo , Nagashima Kei 
Published: June 2021

Purpose We aimed to clarify the effect of estradiol (E2) on heart rates (HR)and arterial pressure (AP), and mechanisms. Methods Female Wistar rats (n=9, age of 7‐9 wk) were bilaterally ovariectomized, and placed a radio transmitter for HR and AP measurements in the abdominal cavity. Two silicon tubes containing E2 were s.c. placed in one group (n=4, E2(+)), and empty tubes for the other (n=5, E2(‐)). The tubes were removed 10 days after the surgery (Day 0). On Day 7 or 21, rats were killed. The left ventricle of heart was taken, and protein contents of β1 and β2‐adrenoreceptors (AR) was determined by Western blotting. Results On Day 0, HR was greater (P<0.05) in the E2(‐) than that in the E2(+) group (388±15 and 337±13 beats/min (bpm) in the light phase; and 450±12 and 390±12 bpm in the dark phase, respectively). On Day 14, HR in the E2(+) group increased (377±15 bpm in the light phase; and 431±14 bpm in the dark phase). On Day 21, HR became lower (P<0.05) in the E2(‐) group (330±17 bpm in the light phase; and 388±20 bpm in the dark phase). Mean AP was not different between the two groups on each day. Both β1‐AR and plasma noradrenaline were greater (P<0.05) in the E2(‐) than E2(+) group, on Day 0. On Day 7, both β1‐AR and plasma noradrenaline decreased, however on Day 21, plasma noradrenaline became higher again. Conclusion A reduction of plasma estrogen level may affect HR, which is resulted from greater sympathetic activity and β1‐AR expression in the heart.Grant Funding Source: This study was supported by MEXT. KIBANKEISEI
Co‐releasing molecules attenuate placental ischemia‐induced hypertension in pregnant rats (1084.4)
Authors: George Eric , Stec David , Granger Joey 
Published: June 2021

Preeclampsia is a serious complication of pregnancy marked by hypertension and maternal endothelial dysfunction. Recently we have published a series of studies demonstrating that induction of heme oxygenase‐1 (HO‐1) could attenuate many of the maternal symptoms of preeclampsia in a rodent model of placental ischemia induced by Reductions on Uterine Perfusion Pressure (RUPP). We have further shown that the individual metabolites of HO‐1, namely CO and bilirubin, both downregulate hypoxia‐induced production of known placental derived pathogenic factors ex vivo. Here, we tested whether , administration of the CO‐releasing molecule CORM‐3 could attenuate the maternal symptoms of placental ischemia. In response to placental ischemia, rats exhibited marked increases in blood pressure compared to control animals (107 ± 1 vs 136 ± 2mmHg, p<0.05). Interestingly, administration of the CO‐releasing molecule CORM‐3 (5mg/kg i.v., qd) significantly decreased blood pressure in both normal pregnant (95 ± 2mmHg) and RUPP (113 ± 1) animals compared to their respective controls. Interestingly, while CORM‐3 had no significant effect on placental VEGF levels, the placental level of the VEGF antagonist sFlt‐1 was markedly increased in control (596 ± 45 vs 1143 ±122 pg/mg, p<0.05) animals, and trended towards increases in RUPP animals (1004 ± 81 vs 1213 ± 72 pg/mg) versus respective controls. This was accompanied by a significant decrease in circulating free VEGF in both Control (527 ± 30 vs 294 ± 9 pg/ml, p<0.05) and RUPP groups (363 ±44 vs 255 ± 23 pg/ml) suggesting that restoration of circulating angiogenic balance in these animals is not the mechanism responsible for their decreased blood pressure.Grant Funding Source: Supported by HL‐108618, HL‐51971 (JPG), HL‐088421, HL‐088421‐S1 (DES), and HL116774 (EMG).
The role of TNF alpha in placental ischemia‐induced cerebrovascular abnormalities (1084.6)
Authors: Warrington Junie , Drummond Heather , Ryan Michael , Granger Joey 
Published: June 2021

While cerebrovascular events contribute to 40% of preeclampsia/eclampsia‐related deaths, the underlying contributing factors are unclear. Circulating tumor necrosis factor α (TNFα) is elevated in women with preeclampsia. We tested the hypothesis that TNFα contributes to cerebrovascular abnormalities that can be prevented by TNFα blockade. TNFα infusion in pregnant rats (100 ng/day ip, from gestational day 14 to 19) increased mean arterial pressure (MAP; 109 ± 3 vs. 99 ± 1 mmHg, p<0.05). Brain water content increased from 78.6 ± 0.1 to 79.0 ± 0.1% in TNFα‐infused rats (p<0.05), mainly due to increases in the anterior brain (79.6 ± 0.3 vs. 78.9 ± 0.1%; p<0.05). TNFα infusion increased hippocampal blood‐brain barrier (BBB) permeability, assayed using Evans blue extravasation, by 89.8 ± 27.2% (p<0.05). To assess the role of endogenous TNFα, a rat placental ischemia model of preeclampsia, induced by reducing uterine perfusion pressure, was treated with the soluble TNFα receptor, etanercept (0.8 mg/kg, sc.) on gestational day 18. Etanercept reduced placental ischemia‐mediated increases in 1) MAP (121 ± 3 to 115 ± 2 mmHg, vs.102 ± 2 in normal pregnant group; p<0.05), 2) anterior brain water content (80.1 ± 0.4 to 79.0 ± 0.2%, vs. 79.2 ± 0.2% in normal pregnant group; p<0.05), and 3) BBB permeability (202 ± 44 to 101 ± 28% of normal pregnant rats). Our results indicate that TNFα may mediate cerebral edema by increasing BBB permeability in response to placental ischemia. Thus, TNFα may be a target for preventing cerebrovascular complications associated with preeclampsia.Grant Funding Source: Supported by: NIH R01 HL108618, PPG HL51971 and AHA 13POST16240000
Complement C5a receptor antagonist attenuates placental ischemia‐induced hypertension in rat (1084.7)
Authors: Peterson Jenna , Lillegard Kathryn , Elmquist Barbara , Gilbert Jeffrey , Regal Jean 
Published: June 2021

Preeclampsia is a pregnancy specific condition characterized by decreased placental perfusion, new onset hypertension, intrauterine growth restriction, decreased free plasma vascular endothelial growth factor (VEGF) and increased innate immune complement system activation producing C3a and C5a. Our previous work demonstrated the importance of complement activation in the reduced uterine perfusion pressure (RUPP) model of placental ischemia‐ induced hypertension in rat. However, the complement activation product important in mediating the hypertension is unclear. Hypothesis: Complement activation product C5a mediates placental ischemia‐induced hypertension independent of changes in free plasma VEGF. On gestation day (GD) 14, rats underwent sham surgery or clip placement on ovarian arteries and inferior abdominal aorta (RUPP) resulting in placental ischemia and increased blood pressure on GD19. The role of C5a was determined by once daily injection of C5a receptor antagonist acetyl‐F‐[Orn‐P‐(D‐Cha)‐WR] (PMX53, 3mg/kg subcutaneous) or vehicle (10% ethanol in saline) on GD14‐18. On GD19, mean arterial pressure (MAP, mmHg) was measured via arterial catheter. Complement activation was monitored by measuring relative serum C3a concentration since C5a was not detectable in serum by current assay methods. VEGF was assessed by ELISA. MAP increased in RUPP (n=23, 108±2) vs. Sham (n=19, 93±2) and PMX53 treatment significantly decreased MAP in RUPP rats (n=11, 101±3) with no effect in Sham (n=5, 93±3). As expected, complement activation increased in RUPP vs Sham (p<0.05). Also, fetal weight and VEGF decreased in RUPP vs Sham (p<0.05). PMX53 treatment did not reverse RUPP‐induced changes in complement activation, fetal weight, or VEGF. These data indicate that C5a in part mediates placental ischemia‐induced hypertension independent of reduced free plasma VEGF.Grant Funding Source: Supported by NIH HL109843
Blockade of the renin angiotensin system abolishes age‐dependent hypertension in female intrauterine growth restricted rats in the absence of an enhanced sensitivity to acute angiotensin II (1085.2)
Authors: Intapad Suttira , Dasinger John , Backstrom Miles , Alexander Barbara 
Published: June 2021

Low birth weight (LBW) as an indicator of poor fetal growth is a risk factor for hypertension. Placental insufficiency induces intrauterine growth restriction (IUGR) in the female rat indicative of LBW. Female IUGR rats exhibit an enhanced sensitivity to acute angiotensin II (Ang II) while remaining normotensive under basal conditions at 4 months of age. Yet, female IUGR rats develop hypertension by 12 month of age. Thus, this study tested the hypothesis that the renin angiotensin system (RAS) contributes to the etiology of age‐dependent hypertension in the female IUGR rat. At 12 months of age rats were treated with vehicle or the ACE inhibitor, enalapril (250 mg/L in drinking water ad libitum), for 2 weeks then mean arterial pressure (MAP) was measured in conscious, chronically instrumented rats. MAP was significantly higher in untreated IUGR versus untreated control rats (134±3 vs. 117±4 mmHg, P<0.05; respectively); enalapril abolished the difference in MAP (118±2 vs. 113±1 mmHg; respectively). Acute infusion (20 min) of Ang II (100 ng/kg/min) increased MAP in all groups (155±3, 164±2, 148±1, 154±2 mmHg; control untreated, IUGR untreated, control treated & IUGR treated; respectively). Yet, the increase in MAP to Ang II was not enhanced in IUGR versus control counterpart. Thus, these data suggest that the RAS contributes to age‐dependent hypertension in the female IUGR in the absence of enhanced sensitivity to Ang II.Grant Funding Source: Supported by HL074927, HL51971, 12POST11980021
Early life stress induces circulating factor(s) promoting endothelial dysfunction (1085.3)
Authors: Ho Dao , Burch Mariah , Musall Benjamin , Pollock Jennifer 
Published: June 2021

In humans, early life stress (ELS) increases cardiovascular disease (CVD) risk and elevates circulating pro‐oxidant factors; however the relationship between ELS‐induced CVD and circulating pro‐oxidant factors is not known. In a mouse model of ELS, maternal separation with early weaning (MSEW), we previously showed that MSEW induces adult endothelial dysfunction. We hypothesized that MSEW promotes endothelial dysfunction by increasing circulating factors that increase superoxide (O2‐) production and reduce NO bioavailability in endothelial cells. MSEW litters underwent maternal separation during postnatal days (PD) 2‐16 for 4‐8h/day, and weaning at PD17. Control (CON) litters remained undisturbed and were weaned at PD21. To determine the impact of MSEW‐induced circulating factors on endothelial function, we incubated Mouse Aortic Endothelial Cells (MAECs) with plasma of CON or MSEW mice (25 ul plasma/ml media; 24 hr). MSEW plasma‐treated MAECs had increased O2‐ levels compared to CON (dihydroethidium‐HPLC; CON = 25.7 + 9.7 vs MSEW = 107.0 + 18.5 pmol/mg pr/hr; p < 0.001). Apocynin (300 μM; NADPH oxidase inhibitor) abolished this effect. However, no change in NO bioavailability (nitrite determination by HPLC) was found. In conclusion, MSEW may promote cardiovascular disease risk by inducing circulating factors that enhance endothelial O2‐ production in an NADPH oxidase‐dependent manner.Grant Funding Source: Supported by NIH grants 1F32 HL116145; P01 HL69999
Maternal western diet primes non‐alcoholic fatty liver disease in adult offspring in mice (1085.4)
Authors: Plosch Torsten , Pruis Maurien , Lendvai Agnes , Zwier Mathijs , de Bruin Alain , Groen Albert K. 
Published: June 2021

Metabolic programming via the maternal diet during gestation may play a role in the development of different aspects of the metabolic syndrome. Using a mouse model we aimed to characterise the role of maternal western type diet in the development of non‐alcoholic fatty liver disease (NAFLD) in the offspring. Female mice were fed either a western (W) or low‐fat control (L) semi‐synthetic diet before and during gestation and lactation. At weaning, male offspring were assigned either the W or the L diet, generating four experimental groups: WW, WL, LW and LL offspring. Biochemical, histological and epigenetic indicators were investigated at 29 weeks of age. Male offspring exposed to prenatal and post‐weaning western‐style diet (WW) showed hepatomegaly combined with accumulation of hepatic cholesterol and triglycerides. This was associated with up‐regulation of de novo lipid synthesis, inflammation and dysregulation of lipid storage. Histopathological analysis revealed the presence of advanced steatohepatitis in WW offspring. In addition, alterations in DNA methylation in key metabolic genes (Ppara, Insig, and Fasn) were detected. In conclusion, maternal dietary fat intake during early development programs susceptibility to liver disease in male offspring, mediated by disturbances in lipid metabolism and inflammatory response. Long lasting epigenetic changes may underlie this dysregulation.Grant Funding Source: Supported by CTMM and NHS
Reduced uterine perfusion pressure alters angiogenic balance in the amniotic fluid and fetal lung of the rat (1085.9)
Authors: Rear Alice , Needham Karen , Lovering Andrew , Regal Jean , Gilbert Jeffrey 
Published: June 2021

Placental ischemia, angiogenic imbalance in the maternal circulation, preterm birth and very low birth weight are characteristic features of preeclampsia. Although recent studies suggest preeclampsia increases risk of the hypoplastic lung disease bronchopulmonary dysplasia (BPD), whether or not chronic placental ischemia results in fetal angiogenic imbalance remains unclear. We hypothesized chronic RUPP would result in decreased expression of angiogenic proteins in the amniotic fluid and fetal lung consistent with the development of BPD. RUPP was induced on gestation day (GD) 14 and fetal lung tissue and amniotic fluid were collected on GD 19 from RUPP and normal pregnant (NP) rats. Fetuses were smaller (1.8 ± 0.19 vs. 2.3 ± 0.08 g; P<0.05) and amniotic fluid free vascular endothelial growth factor (VEGF; 12.6±0.82 vs. 9.19±1.29 pg/ug; P<0.05) decreased in RUPP compared to NP. Soluble fms‐like tyrosine kinase (sFlt‐1) to VEGF ratio was elevated (12.6±0.82 vs. 9.19±1.29; P<0.05) in RUPP versus NP amniotic fluid. VEGF receptor‐2 was decreased (48%; P< 0.05) in lung tissue from RUPP compared to NP fetuses. These data show that chronic placental ischemia results in angiogenic imbalance in fetal tissues similar to that previously observed in the maternal circulation by our group and others. Furthermore, these findings are consistent with the hypothesis that angiogenic imbalance in utero plays an important role in the abnormal vasculogenesis and alveologenesis associated with very low birth weight infants.Grant Funding Source: AHA, NIH