bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial Barrier Restoration after Inflammation‐Induced Hyperpermeability
Authors: Nepali Prerna Ramesh , Mujica Patricio E. , Kim David D. , Thomas Andrew P. , Duran Walter N. 
Published: June 2021

Inflammation is characterized by an increase in endothelial barrier permeability (hyperpermeability) to macromolecules. Major efforts have focused on understanding the mechanisms involved in the hyperpermeability response of endothelial cells; however, less attention has been given to the restoration of vascular barrier integrity following hyperpermeability. Because many negative effects of hyperpermeability are due to its persistence beyond what is required for preserving organ function, we are investigating mechanisms that terminate hyperpermeability and thereby restore microvascular barrier properties. Understanding the mechanisms involved in the restoration of endothelial barrier integrity will have direct clinical impact because sustained inflammation is a hallmark in clinical disorders such as trauma and ischemia‐reperfusion. We demonstrated that eNOS translocation from plasma membrane to cytosol is required for the onset of hyperpermeability. We also demonstrated that stimulation of Epac1 (exchange protein activated by cAMP) contributes to restoration of basal permeability after ischemia‐reperfusion. In this study, we tested the hypothesis that 1) hyperpermeability induces delayed increase in cAMP concentration; and 2) cAMP stimulates Epac1 and VASP (vasodilator‐stimulated phosphoprotein) to promote translocation of eNOS back to the plasma membrane, and restores endothelial barrier properties. We use human microvascular (HMVEC) and mouse myocardial endothelial cells (Myend) to study the restoration of endothelial barrier after hyperpermeability induced by platelet‐activating factor (PAF). Myend VASP knockout (KO) endothelial cells (EC) have significantly greater baseline permeability to macromolecules as well as hyperpermeability response to PAF compared to wild type Myend cells. Stimulation of Epac1 in HMVEC inactivates their hyperpermeability response to PAF. However, Epac1 stimulation fails to inactivate PAF‐induced hyperpermeability in VASP KO Myend EC. PAF activates VASP by phosphorylation at Serine 157 and Serine 239. This phosphorylation is sensitive to eNOS inhibition indicating that PAF stimulates production of eNOS‐derived NO and VASP phosphorylation in a sequential manner. In addition, stimulation of Epac1 after the onset of PAF‐induced hyperpermeability translocates eNOS back from the cytosol to the plasma membrane in HMVEC and in control Myend. eNOS is preferentially located in the cytosol in Myend VASP KO cells. Lack of VASP prevents movement of eNOS associated with stimulation of Epac1. We conclude that VASP is a required protein for movement of eNOS and restoration of EC barrier.Support or Funding InformationRutgers School of Gradute StudiesThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mechanisms of Endothelial Dysfunction in Young Adults with Major Depressive Disorder: Influence of Sex
Authors: Greaney Jody L. , Santhanam Lakshmi , Saunders Erika F. , Alexander Lacy M. 
Published: June 2021

Major Depressive Disorder (MDD) is associated with endothelial dysfunction, a primary causative event in the development of cardiovascular disease. In rodents, depression‐induced endothelial dysfunction is modulated by sex, with females demonstrating less severe impairments than males owing to increased nitric oxide (NO) bioavailability, secondary to greater antioxidant defense mechanisms. This relative preservation of endothelial function in female rodents occurs despite an increased behavioral susceptibility to depressive‐like behaviors. Women of reproductive age are more than twice as likely to suffer from MDD; however, the influence of sex on the molecular mediators of endothelial dysfunction in humans with MDD remains unexplored. We hypothesized that endothelial dysfunction would be less severe in otherwise healthy young women with MDD compared to men with MDD due to increased nitric oxide (NO) bioavailability, mediated by greater antioxidant mechanisms. Twenty healthy adults (HC; 10 men; 22±1 yr) and 23 adults with MDD (9 men; 20±0.3 yr; PHQ‐9 score 12±1) participated. Red blood cell flux (laser Doppler flowmetry) was measured during graded intradermal microdialysis perfusion of the endothelium‐dependent agonist acetylcholine (ACh; 10−10–10−1 M) alone and with the co‐perfusion of the NO synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME; 20 mM), the superoxide dismutase mimetic Tempol (TEM; 10 μM), or the NADPH oxidase inhibitor apocynin (APO; 100 μM). Endothelium‐dependent dilation (EDD) was expressed as a percentage of maximum cutaneous vascular conductance (CVC=flux·mmHg−1). Tissue oxidant stress markers were quantified in cutaneous tissue homogenates (Western blot). As expected, EDD was blunted in MDD and mediated by reductions in NO bioavailability and increases in oxidative stress. There were no sex differences in EDD in either HC (87±6% men vs. 93±9% women; P=0.07) or MDD (79±10% men vs. 76±9% women; P=0.70). In MDD, the NO‐dependent portion of the vasodilatory response was also not different between men and women (14±5% men vs. 16±5% women; P=0.78). Further, pharmacological scavenging of superoxide or inhibition of NADPH oxidase improved EDD to a similar extent men and women with MDD (TEM: 81±7% men vs. 95±3% women, P=0.10; APO: 91±3% men vs. 88±5% women, P=0.65). Nitrotyrosine and NADPH oxidase (p47phox) expression were increased in MDD but not different between sexes (both P>0.05). Although these data confirm significant vascular impairments in MDD via oxidant stress mechanisms, these preliminary findings suggest that sex does not modulate the mechanisms mediating endothelial dysfunction in otherwise healthy young adults with MDD.Support or Funding InformationHL133414This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cyclooxygenase Inhibition and Cerebrovascular Reactivity: Interaction of Aging and Aerobic Fitness
Authors: Corkery Adam T. , Miller Kathleen B. , Howery Anna J. , Carl Alexandra E. , Greisch Mackenzie L. , Eisenmann Nicole A. , Barnes Jill N. 
Published: June 2021

The ability of the cerebral microvessels to respond to chemical or metabolic stimuli declines with age and this change may be one mechanism through which age‐related cognitive decline occurs. Prostaglandins play an important role in the control of vascular tone, therefore changes in prostaglandin synthesis or expression may be underlying the age‐related alterations in cerebral microvascular function. Additionally, we have previously shown that aerobic fitness was associated with a decrease in cerebral microvascular function after cyclooxygenase (COX) blockade; yet this was in a small sample size of healthy older adults who were not exercise trained. Thus, the purpose of our study was to evaluate the effect of age on cerebral microvascular reactivity to hypercapnia (CVR) and to determine if habitual exercise modifies the response to COX blockade. We recruited 45 younger (YA; age = 26±1 y) and 31 older (OA; age = 63±1 y) healthy adults, including 21 sedentary YA, 24 exercising YA, 12 sedentary OA, and 19 exercising OA. Aerobic fitness (VO2 max) was measured during an incremental cycle ergometer test. Middle cerebral artery blood flow velocity (MCAv) and end‐tidal CO2 (ETCO2) were continuously recorded. CVR was calculated as the linear slope of the relationship between ETCO2 and MCAv and was assessed before and after the administration of the COX inhibitor indomethacin (INDO). The change in CVR was calculated as pre INDO CVR – post INDO CVR. There were no group differences in MCAv pre INDO (YA: 65±3 cm/s vs. OA: 59±3 cm/s; p>0.05); however, YA had higher MCAv post INDO (YA: 45±1 cm/s vs. OA: 40±2 cm/s; p<0.05). OA had significantly greater change in CVR compared with YA (2.0±0.1 cm/s/mmHg vs. 1.5±0.2 cm/s/mmHg, respectively; p<0.05). There was also a significant effect of habitual exercise, such that sedentary adults had a greater change in CVR compared with exercising adults (2.0±0.2 cm/s/mmHg vs. 1.5±0.2 cm/s/mmHg, respectively; p<0.05). In addition, there was an inverse association between VO2 max and the change in CVR in OA (r=0.42, p<0.05), but not in YA (p>0.05). Our results indicate that older adults, regardless of exercise status, rely more on COX‐derived products for cerebral microvascular responses to hypercapnia. Our results also suggest that habitual exercise may alter the contribution of COX‐derived products to cerebral blood flow regulation.Support or Funding InformationSupported by National Institute of Health grant HL118154This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Pharmacologically‐induced impairment of neurovascular coupling responses alters gait coordination in mice
Authors: Tarantini Stefano , Yabluchanskiy Andriy , Fulop Gabor Aaron , Hertelendy Peter , Valcarcel‐Ares Marta Noa , Kiss Tamas , Bagwell Jonathan M. , O'Connor Daniel , Farkas Eszter , Sorond Farzaneh , Csiszar Anna , Ungvari Zoltan 
Published: June 2021

There is correlative evidence that impaired cerebral blood flow (CBF) regulation, in addition to promoting cognitive impairment, is also associated with alterations in gait and development of falls in elderly people. CBF is adjusted to neuronal activity via neurovascular coupling (NVC) and this mechanism becomes progressively impaired with age. To establish a direct cause and effect relationship between impaired NVC and gait abnormalities, we induced neurovascular uncoupling pharmacologically in young C57BL/6 mice by inhibiting the synthesis of vasodilator mediators involved in NVC. Treatment of mice with the epoxygenase inhibitor MSPPOH, the NO synthase inhibitor L‐NAME and the COX inhibitor indomethacin significantly decreased NVC mimicking the aging phenotype. Pharmacologically‐induced neurovascular uncoupling significantly decreased the dynamic gait parameter duty cycle, altered footfall patterns and significantly increased phase dispersion, indicating impaired interlimb coordination. Impaired NVC also tended to increase gait variability. Thus, selective experimental disruption of NVC causes subclinical gait abnormalities, supporting the importance of CBF in both cognitive function and gait regulation.Support or Funding InformationThis work was supported by grants from the American Heart Association, the National Center for Complementary and Alternative Medicine, and the National Institute on AgingThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Activation of cannabinoid (CB2) receptors and reactivity of cerebral arterioles
Authors: Mayhan William G. , Arrick Denise M. 
Published: June 2021

While activation of cannabinoid (CB2) receptors has been shown to be neuroprotective, no studies have examined whether this neuroprotection is directed at cerebral arterioles and no studies have examined whether activation of CB2 receptors can rescue cerebrovascular dysfunction during a chronic disease states such as type 1 diabetes (T1D). Our goal was to test that hypothesis that administration of a CB2 agonist (JWH‐133) would improve impaired endothelial (eNOS)‐ and neuronal (nNOS)‐ dependent dilation of cerebral arterioles during T1D. In vivo diameter of cerebral arterioles in nondiabetic and diabetic rats was measured in response to an eNOS‐dependent agonist (adenosine 5′‐diphosphate; ADP), an nNOS‐dependent agonist (N‐methyl‐D‐aspartate; NMDA), and an NOS‐independent agonist (nitroglycerin) before and following JWH‐133 (1 mg/kg IP). Dilation of cerebral arterioles to ADP and NMDA was greater in nondiabetic than in diabetic rats. Treatment with JWH‐133 increased responses of cerebral arterioles to ADP and NMDA in both nondiabetic and diabetic rats. Responses of cerebral arterioles to nitroglycerin were similar between nondiabetic and diabetic rats, and JWH‐133 did not influence responses to nitroglycerin in either group. Thus, it appears that activation of CB2 receptors can influence vascular function of cerebral arterioles during physiologic and pathophysiologic states. We speculate that treatment with CB2 receptor agonists may have potential therapeutic benefits for the treatment of cerebral vascular disease via a mechanism that can increase cerebral blood flow.Support or Funding InformationThese studies were supported by funds from the Diabetes Action Research and Education FoundationThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Inhibition of p70 ribosomal S6 kinase (S6K1) reduces infarct size without improving microregional oxygen supply/consumption balance after cerebral ischemia‐reperfusion
Authors: Weiss Harvey R. , Chi Oak Za , Liu Xia 
Published: June 2021

We tested the hypothesis that inhibition of p70 ribosomal S6 kinase (S6K1) would decrease infarct size and improve microregional O2 supply/consumption balance after cerebral ischemia‐reperfusion. This was tested in isoflurane anesthetized rats with middle cerebral artery blockade for 1 hr and reperfusion for 2 hr with or without PF‐4708671 (S6K1 inhibitor, 75 mg/kg, 15 min after blockade). Regional cerebral blood flow was determined using a C14‐iodoantipyrine autoradiographic technique. Regional small vessel (20–60 μm diameter) arterial and venous oxygen saturations were determined microspectrophotometrically. There were no significant hemodynamic or arterial blood gas differences between groups. The control ischemic‐reperfused cortex had a similar O2 consumption to the contralateral cortex. However, microregional O2 supply/consumption balance was significantly reduced in the ischemic‐reperfused cortex with many areas of low O2 saturation (48 of 80 veins with O2 saturation below 50%). PF‐4708671 did not significantly alter cerebral blood flow or O2 consumption. It also did not affect O2 supply/consumption balance in the reperfused area (41 of 80 veins with O2 saturation below 50%). However, this was associated with a significantly reduced cortical infarct size after S6K1 inhibition (12.9 ± 0.8% control vs 6.6 ± 0.3% PF‐4708671). This suggests that S6K1 inhibition is important for cell survival, but does not significantly improve local oxygen balance after cerebral ischemia‐reperfusion.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Flow‐Mediated Dilation in Obese Adolescents: Correlation with Waist Circumference and Systolic Blood Pressure
Authors: Hussid Maria Fernanda , Jordão Camila Paixão , Lopes‐Vicente Wanda Rafaela , Virmondes Leslie , Cepeda Felipe , Katayama Keyla , Franco‐de‐Oliveira Luis Vicente , de Oliveira Ezequiel F. , Colombo Fernanda Consolin , Trombetta Ivani Credidio 
Published: June 2021

BackgroundThe increasing prevalence of obesity worldwide impacts childhood and adolescence, and this trend points to a significant growth rate of non‐transmissible chronic diseases in the near future. Endothelial dysfunction is an early marker of cardiovascular risk.ObjectiveTo determine a) whether obese adolescents have endothelial dysfunction and b) whether cardiovascular risk factors and obstructive sleep apnea (OSA) are associated with endothelial dysfunction.MethodsWe studied 20 obese adolescents (OA; median age 14 years, 100.9±20.3 kg), post pubescent, sedentary, not following any special diet or receiving any drug treatment, and compared them with 10 lean adolescents (LA, median age 15 years, 54.4±5.3 kg) paired for sex. Metabolic syndrome risk factors (MetS, International Diabetes Federation), vascular function (flow‐mediated dilation, FMD, and Reactive Hyperemia Index, RHI, by peripheral arterial tonometry, EndoPAT®), functional capacity and OSA using the apnea‐hypopnea index (AHI, polysomnography) were assessed.ResultsThe OA presented higher waist (WC) and cervical circumference, as well as higher proportion of body fat, triglycerides, SBP, DBP, LDL‐c and lower HDL‐c than the LA group. In the OA, 35% presented MetS, which was absent in the LA group. OSA was present in 86.6% of the OA and 50% of LA (AHI>1 event/hour). There was no difference between groups in the AHI, VO2 peak and RHI. The OA presented lower FMD than LA (6.17±2.72 vs. 9.37±2.20%, p=0.005). There was an association between FMD and WC (r=−0.506, p=0.008) and FMD and SBP (r=−0.493, p=0.006).ConclusionOSA was observed in most adolescents, regardless of obesity. OA presented MetS and endothelial dysfunction. Increased WC and SBP seem to be involved in this alteration.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Mouse strains, sex, salt intake, AT1R activity and blood pressure
Authors: Wang Xiaoyan , Ma Xiaobo , Asico Laureano , Armando Ines , Jose Pedro 
Published: June 2021

Male C57Bl/6J mice are salt‐sensitive while male SJL/J mice are salt‐resistant which is related to the functional state of the renal dopamine D1 receptor (D1R). Angiotensin II may be involved in the decreased renal expression of D1R of salt‐sensitive obese Zucker rats. However, the roles of the duration and amount of dietary salt intake and sex on salt sensitivity are not well known. Therefore, we studied the effect of sodium intake (<0.009, 0.6, 0.8,1.6, 4, 6, % NaCl) on the blood pressure (BP), renal dopamine and angiotensin receptors and sodium transporters in three different strains of male and female mice. We found that 4 or 6% NaCl diet given for 1 or 3 wks increased the BP of male C57Bl/6Jackson but not C57Bl/6Taconic, Balb/c, or SJL/J mice. The male C57Bl/6J mice with NaCl intake equal to or greater than 1.6% had increased BP. Similar to that reported in male C57Bl/6J mice, the BP (telemetry) of female C57Bl/6J mice was also increased by 4% NaCl diet (1 wk) which is associated with a decrease in serum renin but an increase in renal protein expression of angiotensin type 1 (AT1R). The salt‐induced increase in BP was ameliorated by angiotensin type 1 (AT1R) blockade with candesartan (1 mg/kg/day, subcutaneously administered with osmotic mini‐pumps, 1 wk) in both sexes. Except for the lower body weight of female than male mice, as expected, there were no differences in food/water intake, urinary excretions of water and electrolytes, and serum concentrations of creatinine and electrolytes, regardless of diets. In female C57Bl/6J mice on 6% NaCl diet, candesartan increased renal D1R and D5R but not D2R, D3R, or D4R protein expression while male C57Bl/6J mice had increased renal D5R protein expression, only. There was a similar decrease in renal protein expressions of sodium‐hydrogen exchanger isoform 3, sodium‐potassium‐2 chloride cotransporter, sodium‐chloride cotransporter, and α, β and γ epithelial sodium channel (ENaC) but not type 2 sodium phosphate cotransporter and α1Na+K+ATPase, in both male and female mice. We conclude that the salt sensitivity of BP of C57BL6/J mice is not sex‐related. However, the amelioration of high salt induced‐hypertension by AT1R blockade may be mediated by the differential increase in renal dopamine receptor expression and similar reduction in renal apical sodium transporters, leading to a decrease in renal sodium transport in male and female mice.Support or Funding InformationThis work was supported in part by grants from the National Institutes of Health, HL68686, HL23081, HL074940, HL092196, and DK039308. Dr. Xiaoyan Wang was supported, in part, by National Kidney Foundation of Maryland (Professional Development Award, 2014).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effect of Dietary Sodium Intake on Blood Pressure Variability
Authors: Migdal Kamila U. , Watso Joseph C. , Babcock Matthew C. , Robinson Austin T. , Wenner Megan M. , Stocker Sean D. , Farquhar William B. 
Published: June 2021

PurposeStudies in rodents have demonstrated that increased dietary sodium intake elevates blood pressure variability (BPV), independent of changes in resting blood pressure. Clinical studies have shown that increased BPV independently contributes to target organ damage and cardiovascular events. However, the effects of high dietary sodium intake on BPV in young, normotensive adults remains unknown. Therefore, the purpose of this study was to test the hypothesis that increased dietary sodium intake alters BPV in young, healthy adults.MethodsFourteen healthy, normotensive adults (7M/7W; age: 25±4 yrs; BMI: 24.7±0.9 kg/m2, Mean‐±SEM) participated in a controlled feeding study that consisted of 10 days of either low‐(LS:1 g sodium/day), medium‐ (MS: 2.3 g sodium/day), or high‐sodium (HS: 7 g sodium/day) diets, in randomized order. The diets were separated by at least a month. Urinary sodium excretion was determined to ensure compliance on diets. Resting beat‐to‐beat BPV was assessed in the laboratory in the supine position for ten minutes. BPV was also derived from 24‐hour ambulatory blood pressure monitoring (ABPM) to assess BPV under free‐living conditions. BPV was calculated as the average real variability index (ARV; the average of the absolute differences between consecutive blood pressure measurements) and as standard deviation (SD).ResultsTwenty‐four‐hour urinary sodium excretion increased in a step‐wise manner from low, to the medium, to the high sodium diets (LS: 34±6 mmol/24 hours, MS: 93±9 mmol/24, HS:275±29 mmol/24 hours, p<0.05). Dietary sodium did not alter laboratory beat‐to‐beat systolic ARV (LS=2.2±0.2 mmHg, MS= 2.0±0.2 mmHg, HS= 2.1±0.2 mmHg, p>0.05) or 24h ABPM systolic ARV (LS=9.4±0.5 mmHg, MS= 9.9±0.4 mmHg, HS=10.3±0.7 mmHg, p>0.05). Dietary sodium also did not alter laboratory beat‐to‐beat systolic SD (LS= 5.4±0.5 mmHg, MS=5.1±0.3 mmHg, HS=5.8±0.6 mmHg, p>0.05) or 24h ABPM systolic SD (LS= 12.1±0.9 mmHg, MS= 13.9±0.7 mmHg, HS= 13.1±0.9 mmHg, p>0.05).ConclusionThese preliminary data suggest that 10 days of high dietary sodium intake does not alter systolic BPV in young, healthy adults.Support or Funding InformationNIH Grant 1RO1HL128388This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.