bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Serelaxin on Renal Microcirculation in Rats under Control and High Angiotensin Environments
Authors: Shao Weijian , Prieto Minolfa C. , Gonzalez‐Arancibia Camila , Navar L. Gabriel 
Published: November 2023

Serelaxin is a novel recombinant human relaxin‐2 that is being investigated for the treatment of heart failure. However, the effects on renal function, especially on renal microcirculation remain uncertain. Immunofluorescence studies localized RXFP1,2 and 3 receptors on endothelial cells, vascular smooth muscle cells, mesangial and collecting duct cells. Therefore we investigated the effects of serelaxin on the renal microvasculature under normal conditions and in presence of exogenous angiotensin (Ang) II levels. Clearance experiments were performed in male pentobarbital anesthetized Sprague‐Dawley normotensive (n=5) and Ang II infused rats (3ng/min, n=5). In control rats, serelaxin (5ug/100g body weight/hr) significantly increased mean arterial pressure (119±1.7 vs. 135±1.1 mmHg; P<0.05), renal blood flow (7.5±0.2 vs. 9.5±0.2 ml/min/g; P<0.05), urine flow (5.1±0.1 vs. 9.9±0.9 μl/min/g; P<0.05) and sodium excretion rates (0.12±0.01 vs. 2.15±0.19 μmol/min/g; P<0.05) without significant changes in GFR (1.26±0.04 vs. 1.38±0.03 ml/min/g). During infusion with subthreshold Ang II infused rats, serelaxin did not alter mean arterial pressure (122±1.3 vs. 126±0.7 mmHg), renal blood flow (9.3±0.2 vs. 10.1±0.3 ml/min/g) or urine flow (4.7±0.2 vs. 4.9±0.3 μl/min/g). However, the increases in sodium excretion rate were sustained (0.4±0.05 vs. 1.18±0.16 μmol/min/g; P<0.05). Serelaxin did not significantly alter GFR in Ang II infused rats (1.27±0.12 vs. 1.4±0.09 ml/min/g). Heart rates were elevated by serelaxin infusion in both control rats (373±8.2 vs. 508±2.9 beat/min; P< 0.05) and in Ang II infused rats (460±7.4 vs. 512±5.1 beat/min; P<0.05). Using the in vitro isolated juxtamedullary nephron preparation, the effects of serelaxin on afferent and efferent arteriolar diameters from control rat kidneys and during Ang II superfusion were assessed with videomicroscopy. In control rat kidneys, serelaxin (20, 40 ng/ml infusion in blood) significantly dilated afferent arterioles (10.8±1.2 vs. 12.2±1.2 and 13.7±1.2 μm; n=5; P<0.05) and efferent arterioles (9.7±0.9 vs. 11.4±1.1 and 12.0±0.9 μm; n=5; P<0.5). During Ang II superfusion (0.5nM), serelaxin (20, 40 ng/ml infusion in blood) had no effects on afferent arteriolar diameters (11.5±0.1 vs. 11.7±0.1, 11.8±0.1 μm; n=4). These results demonstrate that serelaxin has direct dilating actions on both pre‐ and post‐glomerular arterioles. In the presence of exogenous Ang II levels, the effects of serelaxin were prevented. The responses of the renal microvasculature may be related to changes in NO bioavailability and oxidative stress. In conclusion, serelaxin increases overall renal blood flow, urine flow and sodium excretion by dilating both pre and post glomerular arterioles in control conditions, but these effects are attenuated in the presence of exogenous Ang II.Support or Funding InformationThis study was supported by Novartis Pharmaceuticals Corporation.
Role of cerebrovascular endothelial dysfunction and oxidative/nitrative stress in impaired functional hyperemia: implications for age‐related vascular cognitive impairment
Authors: Tarantini Stefano , Toth Peter Joseph , Davila Antonio , Valcarcel‐Ares Marta Noa , Tucsek Zsuzsanna , Varamini Behzad , Ballabh Praveen , Sonntag William E , Baur Joseph A , Csiszar Anna , Ungvari Zoltan 
Published: November 2023

Previous studies demonstrate that aging and pathological conditions associated with accelerated cerebromicrovascular aging (e.g. hypertension, obesity) promote cerebrovascular dysfunction by decreasing bioavailability of NO and increasing production of O2. − and reactive nitrogen species. Impairment of moment‐to‐moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of cognitive impairment associated with the aforementioned conditions and previous studies demonstrate that endothelial dysfunction plays a critical role in neurovascular uncoupling in these conditions. Despite these advances, the role of endothelial NO mediation in neurovascular coupling responses is not well understood. To establish the link between endothelial function and functional hyperemia, neurovascular coupling responses were studied in mutant mice overexpressing or deficient in eNOS and the role of P2Y1 receptors in purinergic glioendothelial coupling was assessed. We found that genetic depletion of eNOS (eNOS−/−) and pharmacological inhibition of NO synthesis significantly decreased the CBF responses in the somatosensory cortex evoked by whisker stimulation and by administration of ATP, mimicking oxidative/nitrative stress‐mediated impairment of functional hyperemia and microvascular endothelial responses observed in aged mice. Overexpression of eNOS enhanced NO mediation of functional hyperemia. In control mice the selective and potent P2Y1 receptor antagonist MRS2179 attenuated both whisker stimulation‐induced and ATP‐mediated CBF responses, whereas in eNOS−/− mice the inhibitory effects of MRS2179 were blunted. Collectively, our findings provide additional evidence for purinergic glio‐endothelial coupling during neuronal activity, highlighting the role of ATP‐mediated activation of eNOS via P2Y1 receptors in functional hyperemia.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 Aging
Mitochondrial Mechanisms of Nelfinavir Toxicity in Human Brain Microvascular Endothelial cells
Authors: Unis Graham , Baker Tyler P , Rajaprabhakaran Gowthamram , Sure Venkata N , Jain Neelesh P , Abraham Vihas M , Peterson Nicholas R , Gordon Angellica O , Chen Allen L , Cama Zeinab , Mondal Debasis , Katakam Prasad VG 
Published: November 2023

Antiretroviral therapies with combinations of mechanistically different classes of drugs resulted in reduced HIV‐associated neurocognitive disorders, however, milder forms of cognitive disorders continue to be disabling in AIDS patients. Toxicity resulting from long‐term use of antiretroviral drugs have been implicated in the cognitive disorders but the exact underlying mechanisms are poorly understood. We hypothesized that nelfinavir, a protease inhibitor, causes the disruption of blood brain barrier (BBB) by promoting mitochondrial oxidative stress and impairing mitochondrial respiration. Our studies examined the effects of nelfinavir in human brain microvascular endothelial cells (BMECs). Cell viability following 48 h Nelfinavir treatment of hBMECs was determined using CCK‐8 assay. Measurements of superoxide levels were made by electron spin resonance spectrometery using spin probes for total (1‐Hydroxy‐3‐methoxycarbonyl‐2,2,5,5‐tetramethyl‐pyrrolidine) and mitochondrial superoxide (mito‐Tempo‐H). Oxygen consumption rates (OCR) were measured by Seahorse Analyzer. Transcellular endocytosis measurements were performed by using 40 kDa‐FITC‐dextran transfer in BMECs grown in transwells. Nelfinavir treatment caused an increase in cell proliferation of BMECs at low doses (0.5 μM‐1.5 μM) but decreased viability at high doses (5 μM‐10 μM). Nelfinavir at therapeutic doses promoted the generation of total and mitochondrial superoxide in BMECs. In addition, nelfinavir dose‐dependently diminished the basal OCR and reserve mitochondrial respiratory capacity in BMECs. Moreover, nelfinavir dose‐dependently promoted increased transcellular permeability in BMECs. Thus, nelfinavir induced mitochondrial oxidative stress promotes diminished mitochondrial respiratory capacity and decreased cell proliferation leading to the disruption of BBB.Support or Funding InformationSupport: PVK: Louisiana BoRSF‐RCS (LEQSF(2014‐17)‐RD‐A‐11) and AHA Scientist Development Grant (14SDG20490359); IR: AHA Postdoctoral Fellowship Grant (15POST23040005); and DWB: NIH grants (HL‐077731and HL093554).
Cardiovascular Implications of Environmental Stressors, a Health Call to Protect the Planet
Authors: Cabrales Pedro , William Alexander 
Published: November 2023

A class of air pollutants known as atmospheric ligands (oxygen, O2; carbon monoxide, CO; nitric oxide, NO; and hydrogen sulfide, H2S) are associated to a variety of physiological process. At atmospheric concentrations below regulatory limits, these atmospheric ligands can be physiologically active. Previous studies have examined their implication on cardiovascular health outcomes at concentrations above US Environmental Protection Agency (EPA) limits. Our studies have focused on cardiovascular effects these gases within good to moderate EPA limits. Hamsters instrumented with dorsal window chambers, or with a miniaturized left ventricle pressure volume (LVPV) were used to study microvascular and systemic implications of acute and chronic exposure to these gases. Our results present the implications of atmosferic polutans on cardiovascular function. Due to the direct implications on health, humanizing the protection of the planet will emphasize the gravity of environmental preservation.Support or Funding InformationP01‐HL110900, R01‐HL52684, and R56‐HL123015.
Nocturnal Blood Pressure Dipping in Normotensive Adults: Effect of Dietary Sodium and Sex
Authors: Brian Michael , Dalpaiz Ameg , Matthews Evan , Lennon‐Edwards Shannon , Edwards David , Farquhar William 
Published: November 2023

Normal nocturnal blood pressure (BP) dipping is arbitrarily defined as a decrease in mean daytime to mean nighttime BP by 10% to 20%. Individuals that have impaired nocturnal BP dipping (i.e., <10%) have an increased risk of cerebrovascular and cardiovascular diseases. Excess sodium consumption is associated with increased cardiovascular disease risks and no studies have examined nocturnal BP dipping under a controlled sodium diet.PURPOSETo assess nocturnal BP dipping during low (LS) and high sodium (HS) diets in men and women. We hypothesized that a HS diet would impair nocturnal BP dipping, and men would have a greater impairment than women.METHODSEighty‐seven healthy normotensive men (n = 41; age: 35 ± 2 years) and women (n = 46; age: 40 ± 2 years) participated in a controlled feeding study where LS (20 mmol Na+/day) and HS (300 mmol Na+/day) diets were provided for 7 days each in random order. Subjects wore a 24‐hour ambulatory BP monitor, and we collected a 24‐hour urine sample and fasted blood sample on the final day of each diet. Nocturnal BP dipping was calculated as: ((mean daytime BP – mean nighttime BP)/mean daytime pressure)*100.RESULTSAs expected, there was a significant increase in urinary sodium excretion during the HS diet (women: LS = 26.0 ± 2.1 vs. HS = 238.4 ± 14.1 mmol/24hr; men: LS = 31.5 ± 4.4 vs. HS = 234.4 ± 13.3 mmol/24hr; p < 0.01) and serum sodium (women: LS = 137.7 ± 0.3 vs. HS = 139.7 ± 0.2 mmol/L; men: LS 137.9 ± 0.4 vs. HS = 139.8 ± 0.3; p < 0.05) with no differences observed between the sexes. Nocturnal BP dipping was not different between the diets (women: LS = 10 ± 1% vs. HS = 10 ± 1% mmHg; men: LS = 9 ± 1% vs. HS = 10 ± 1% mmHg; p > 0.05) with no differences observed between the sexes.CONCLUSIONOur findings suggest that increased dietary sodium does not influence nocturnal BP dipping responses in normotensive men and women.Support or Funding InformationNIH Grant R01 HL104106
Divergent response of circulating CTRP3 levels to obesity between males and females
Authors: Peterson Jonathan M. , Wagner Roy Marshall , Sivagnanam Kamesh , Clark William Andrew 
Published: November 2023

C1q TNF alpha related Protein 3 (CTRP3) is a novel adipose tissue derived secreted factor, or adipokine. CTRP3 has been linked to a number of beneficial biological effects on metabolism, inflammation, and survival signaling in a variety of tissues. However, very little is known about CTRP3 in regards to human health. The purpose of this project was to examine circulating CTRP3 levels in a clinical population. It was hypothesized that serum CTRP3 levels would be decreased with obesity and diabetes.Methodsbody mass index (BMI), diabetes status, and plasma samples were collected from 100 patients who were >30 years of age and presented at the East Tennessee State University Heart Clinic with symptoms requiring heart catheterization in order to identify the presence of cardiovascular blockages (n=51 male, n=49 female). Circulating CTRP3 levels were quantified using commercially available ELISA.ResultsCirculating concentrations of CTRP3 were significantly higher in normal weight (BMI <30) females (1.65 ± 0.24 μg/ml) compared with males (1.05 ± 0.12 μg/ml). Interestingly obesity (BMI >30) resulted in an increase in circulating CTRP3 levels in male subjects (1.52 ± 0.16 ug/ml) but showed a significant decrease in female subjects (1.11 ± 0.15 μg/ml). Additionally, there was a significant reduction in circulating CTRP3 levels in female subjects who were diagnosed with diabetes compared with patients without diabetes (1.50 ± 0.12 vs. 0.812 ± 0.10 μg/ml). There was no relationship between diabetes status and circulating CTRP3 levels in male subjects.ConclusionCirculating CTRP3 levels had a different relationship with diabetes and obesity status between male and female patients. It is possible that circulating CTRP3 levels are controlled by hormonal status, however more research is needed to explore this relationship.Support or Funding InformationCollege of Clinical and Rehabilitative Health Sciences, East Tennessee State University, Dean's Student Research Award
Wild Type p53 Regulates Endothelial Barrier Function by mediating Rac1 signaling and inhibiting RhoA activity
Authors: Barabutis Nektarios , Birmpas Charalampos , Thangjam Gagan , Gregory Betsy W , Clements Mary Ann , Newton Joseph , Catravas John D. 
Published: November 2023

The tumor suppressor and heat shock protein 90 (hsp90) client protein, p53, is a transcription factor which is frequently mutated in human cancers. An emerging body of evidence suggests that p53 also induces strong anti‐inflammatory responses, both in vivo and in vitro. Such activities maintain and preserve vascular barrier function, a key element of lung integrity and defense against endogenous or exogenous insults. We have recently reported that p53 is a major regulator of vascular integrity and endothelial permeability mostly due to its inhibition of the barrier disruptive RhoA signaling. In the present study we further investigated the mechanisms underlying the barrier protective effects of p53. Nutlin‐ or hsp90 inhibitor‐ induced p53 overexpression increased Rac1 activity (GTP‐bound Rac1), a small GTPase with known barrier‐protective effects. Nutlin or hsp90 inhibitor also increased downstream LIMK1/2 phosphorylation/activation as well as cofilin phosphorylation/deactivation thus preventing actin stess fiber formation and promoting cortical actin. When p53 expression was suppressed by siRNA, the opposite effects were observed. Hsp90 inhibitor (AUY‐922)‐induced p53 overexpression also caused an induction of the RhoA negative regulator p190Rho‐GAP that led to inhibition of RhoA activity as well as inhibition of downstream MLC phosphorylation. Real time measurements of endothelial barrier function by continuous monitoring of transendothelial electrical resistance (TER) of human lung microvascular endothelial monolayers revealed a prominent role of p53 in endothelial barrier regulation. Downregulation of p53 by pifithrin attenuated AUY‐922‐induced barrier enhancement, whereas siRNA‐mediated p190Rho‐GAP silencing led to an enhanced LPS‐induced decrease in TER. In conclusion, we propose that p53 regulates vascular barrier function by manipulating the balance of the actin remodeling Rac1 and RhoA pathways.Support or Funding InformationThis study was supported by National Heart, Lung, and Blood Institute Grants HL101902 and HL93460.
Sex Differences in Hypertension: A Modeling Study
Authors: Chen Ying , Edwards Aurelie , Sullivan Jennifer , Layton Anita 
Published: November 2023

The goal of this study was to investigate sex differences in spontaneously hypertensive rats (SHR) and their effects on medullary oxygenation and oxidative stress. To accomplish that goal, we developed a detailed mathematical model of solute transport in the renal medulla of the rat kidney. The model represents the radial organization of the renal tubules and vessels, which centers around the vascular bundles in the outer medulla and around clusters of collecting ducts in the inner medulla. In addition, the model accounts for the biochemical reactions among O2, nitric oxide (NO), and superoxide (O2−). Model simulations yield significant radial gradients in interstitial fluid oxygen tension and NO and O2− concentration in the outer medulla and upper inner medulla. We conducted model simulations to assess the extent to which sex differences in SHR, including O2− production rate and anti‐oxidant capacity, contribute to the higher levels of oxidative stress and the lower levels NO bioavailability reported in male SHR.Support or Funding InformationThis research was supported in part by NIH grant DK‐89066.
ACE2 Deletion is Associated with Increased ADAM17 and Reduced Inhibitory Currents to Pre‐sympathetic Hypothalamic Neurons
Authors: Mukerjee Snigdha , Xu Jiaxi , Sriramula Srinivas , Gao Hong , Zsombok Andrea , Lazartigues Eric 
Published: November 2023

Deletion of the Angiotensin Converting Enzyme type 2 (ACE2) leads to a genetic background‐dependent increase in baseline blood pressure in mice, which can reach hypertensive levels with age. Recently, we identified a disintegrin and metalloprotease 17 (ADAM17) as a new member of a signaling pathway leading to the development of neurogenic hypertension. In an attempt to pinpoint the origin of developing hypertension in ACE2 knockout mice, we hypothesized that enhanced sympathetic drive could originate from elevated ADAM17 in pre‐sympathetic neurons of the paraventricular nucleus (PVN) of hypothalamus. Adult (10–12 week‐old) wildtype (WT) and ACE2 knockout male mice were used to assess ADAM17 protein expression (immunohistochemistry, Western blot and qPCR) in the PVN while another group was injected in the kidney with a pseudorabies virus encoding a green fluorescent protein, for retrograde labeling of sympathetic neurons. After 4 days, whole‐cell patch‐clamp recordings were conducted from labeled pre‐sympathetic PVN neurons. The resting membrane potential of pre‐sympathetic PVN neurons in WT mice was −49.01 ± 2.09 mV, while −48.9 ± 0.2 mV in ACE2 knockout mice, which may suggest an increased threshold for excitability in pre‐sympathetic PVN neurons. Interestingly, when the inhibitory inputs were analyzed, miniature IPSC frequency was reduced in ACE2 KO compared to WT (0.68 ± 0.29 vs. 1.56 ± 0.28 Hz; P<0.05) suggesting that the ACE2 knockout mice might be more susceptible to excitation, thus contributing to a sympathetic overdrive. Within the hypothalamus, ADAM17 expression showed a 2‐fold increase in ACE2 knockout compared to WT mice (P<0.05). Using immunohistochemistry, increased ADAM17 expression was confirmed in parvocellular neurons of the PVN. Taken together, our data suggest that enhanced expression of ADAM17 in the parvocellular region of the PVN could be associated with increased excitability of pre‐sympathetic neurons in ACE2 knockout mice. This dysregulation in neuronal activity might alter the intricate pressor homeostasis leading to increased blood pressure. These results suggest that ADAM17 could be a potential new target for the reduction of enhanced sympathetic activity in neurogenic hypertension.Support or Funding InformationNIH/NHLBI (HL093178) COBRE (P30GM106392)
G Protein‐Coupled Estrogen Receptor (GPER) Expression in The Kidney Of L‐NAME‐Induced Hypertension and 2K‐1C Rats
Authors: de Oliveira Sales Elizabeth Barbosa , Maruyama Nadia Oliveira , Varela Vanessa Araujo , Lucas Thais F. , Boim Mirian Aparecida , Porto Catarina Segreti , Bergamaschi Cassia Toledo , de Campos Ruy Ribeiro 
Published: November 2023

Recent studies show that estrogen plays an important role in the structural and functional processes of the central nervous system and peripheral organs in the control of blood pressure. And also, provides renoprotective effects, which are dependent on the direct action of G protein‐coupled estrogen receptor (GPER) in the renal tubules. Here we evaluated the GPER protein expression levels and its location in the kidneys of rats with L‐NAME‐induced hypertension (n=6), 2 Kidney‐1Clip (2K‐1C) hypertension (n=5) and 2K‐1C treated with Losartan (n=5). The rats were treated with L‐NAME (20mg/Kg/day) and Losartan (30mg/Kg/day) by gavage for 7 consecutive days. The systolic blood pressure (SBP) was monitored using tail cuff recording method before and after the treatment to confirm the levels of blood pressure. The hypertension induced by L‐NAME was followed by up regulation of GPER (74,8%) in the kidney compared to SHAM group analyzed by western blotting. In addition, the immunohistochemistry analyses showed that this GPER increase was specific to renal medulla in this animals (L‐NAME: 32,5 % ± 2,6 vs. SHAM: 19,0 % ± 0,5). However, a significant decrease in GPER was showed in clipped kidney compared to the contralateral kidney in 2K‐1C model (Clipped: 110,0 % ± 5,8 vs. Contralateral:7 5,1% ± 6,5). And also, this reduction was specific to renal medulla in the clipped kidney (Contralateral: 14,6 % ± 0,6 vs. Clipped: 10,2 ± 1,6, P<0,05). Despite the Losartan reduced of SBP, the treatment unchanged the GPR30 expression in the kidney of 2R‐1C animals. Therefore, our findings suggest that the GPER shows protective function by increasing its expression in the hypertensive rats treated with L‐NAME. On the other hand, the reduction of GPER in the clipped kidney could be involved in the deleterious effects of renovascular hypertension on this organ. The mechanisms by which the GPER is modulated still need to be further investigated. However, our results demonstrate that GPER is not dependent of Ang II in renal tissue of renovascular animals.Support or Funding InformationSupported by CAPES and FAPESP.
P2X Receptor‐Mediated Inhibition Of NaCl Absorption In The Thick Ascending Limb: No Evidence For Nitric Oxide As Second Messenger
Authors: Svendsen Samuel Levi , Olsen Jeppe Steen , Preatorius Helle , Leipziger Jens G 
Published: November 2023

BackgroundBasolateral (bl.) P2X receptors acutely and markedly reduce NaCl absorption in mouse medullary thick ascending limb (mTAL). It has been proposed that P2X receptor mediate NO synthesis and subsequent NKCC2 inhibition. P2X receptor stimulation causes an increase in cytosolic Ca2+ and therefore this could be proximal to the generation of NO.ObjectiveHere we tested if blocking NO synthesis, adding an NO donor or hindering Ca2+ influx affects the ATP‐mediated (P2X) transport inhibition.MethodsWe used isolated, perfused mTALs from mice to electrically measure NaCl absorption. By microelectrodes we determined the transepithelial voltage (Vte) and the transepithelial resistance (Rte) and via these the transepithelial Na+ absorption (equivalent short circuit current, I′sc).ResultsWe confirm that bl. ATP (100μM) induced a marked, acute and reversible inhibition of Na+ absorption (28% ± 6%, n=6). In the presence of the NO synthase blocker L‐NAME (100 μM, ~4 min preincubation) the ATP effect remained unaffected (23% ± 9%, n=6). Also higher concentrations and longer incubation with L‐NAME (1 mM, 15min incubation) were without effect. High concentrations of L‐NAME (1 mM) per se reduced transport significantly. Acute addition of the NO donor SNAP (100μM, ~10 min) did not affect tubular transport. Furthermore, the removal of extracellular Ca2+ (100 nM, 2 min preincubation) had no effect on the ATP‐induced transport inhibition ([Ca2+ ]o=100nM: 21% ± 6%, n=5, [Ca2+]o=1μM: 24% ± 4%, n=6).ConclusionWe find no evidence for nitric oxide (NO) as second messenger for P2X receptor‐dependent transport inhibition. Similarly, Ca2+ signaling appears not involved in the ATP effect. It remains undefined how P2X receptors trigger the marked reduction of transport in the TAL.