Abstract MP28: UBR1 And BRCC36 Regulate ACE2 Ubiquitination And Deubiquitination In Ang-II Induced Hypertension.

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Navya Lakkappa ◽  
Clara Berdasco ◽  
Catalin Filipeanu ◽  
Eric D Lazartigues
Keyword(s):  
New Orleans ◽  
Therapeutic Strategy ◽  
Fold Increase ◽  
Bioinformatic Analysis ◽  
Washington Dc ◽  
Ang Ii ◽  
Howard University ◽  
Fold Reduction ◽  
Induced Hypertension ◽  
One Way Anova

UBR1 and BRCC36 regulate ACE2 Ubiquitination and Deubiquitination in Ang-II induced Hypertension. Navya Lakkappa 1 , Clara Berdasco 1 , Catalin Filipeanu 2 , Eric Lazartigues 1 1. Pharmacology, LSUHSC, New Orleans, LA; 2. Pharmacology, Howard University, Washington, DC. ACE2 is undergoing Ang-II-mediated internalization, ubiquitination and degradation, contributing to hypertension. Using proteomics and bioinformatic analysis, we identified UBR1 and BRCC36 and evaluated their role in ACE2 ubiquitination in hypertension. Following gonadectomy, blood pressure (BP, telemetry) was recorded in C57BL6/J mice (3-month-old, n=10/group) infused with Ang-II (490 ng/Kg/min/4 weeks sc). UBR1, BRCC36 and ACE2 expression was assessed in heart and kidneys (capillary western). Ang-II infusion induced a significant mean BP increase in all groups (sham males: 133 ±0.6; castrated: 141 ±0.6; sham females: 134 ±0.7; ovariectomized: 130 ±0.3 mmHg; n=6, one-way ANOVA, P<0.001). UBR1 levels were similar between sexes while cardiac BRCC36 was 2-fold higher in females (P<0.001). Ang-II-mediated hypertension led to a 4-fold increase in UBR1 in males heart and kidneys (P<0.001) and a 2-fold increase in females (P<0.01) while gonadectomy blunted this effect by 50%. Castration did not affect BRCC36 levels while ovariectomy reduced them by 5-fold. Males infused with Ang-II showed no significant change in BRCC36 expression while hypertensive females had a dramatic reduction (5-fold, P<0.001) in the heart. Overall, UBR1 was associated with a reduction and BRCC36 was associated with an increase of ACE2 levels. Endothelial cells (HAEC) exposed to Ang-II (100 nM for 4h) had a 2-fold increase in UBR1 and a 10-fold reduction in ACE2 (n=3: one-way ANOVA, P< 0.01). Complete knockdown of UBR1 resulted in a 10-fold increase in ACE2 levels (n=3: one-way ANOVA, P<0.05). In HEK293T cells transfection with BRCC36 reversed the Ang-II effects (72533.5 ±4432.2 vs. 42204.2 ±4338.7; FU/min/μg protein, n=3, one-way ANOVA, P<0.05). Together, we show that ACE2 expression in hypertension is differentially regulated by URB1 and BRCC36 and depends on sex hormones. Inhibition of UBR1 and upregulation of BRCC36 could be a new therapeutic strategy to prevent ACE2 ubiquitination in hypertension.

scholarly journals Glutamate and γ-aminobutyric acid differentially modulate glymphatic clearance of amyloid β through pulsation- and aquaporin-4 dependent mechanisms

2020 ◽  
Author(s):  
Cheng Wu ◽  
Yi-wei Feng ◽  
Qun Zhang ◽  
Feng-yin Liang ◽  
Yue Lan ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Amyloid Β ◽  
Aquaporin 4 ◽  
Aminobutyric Acid ◽  
Dependent Manner ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Effective Therapeutic Strategy ◽  
Glymphatic Pathway ◽  
The Brain

AbstractThe glymphatic system contributes to a large proportion of brain waste clearance, including removal of amyloid β (Aβ). We have demonstrated that glutamate and γ-aminobutyric acid (GABA) influence glymphatic clearance through distinct mechanisms whereby GABA exerts modulatory effects in an aquaporin-4 (AQP4)-dependent manner while the actions of glutamate are pulsation-dependent. The efficacy of GABA and glutamate in alleviating Aβ in APP-PS1 and Angiotensin-II (Ang-II) induced hypertension mouse models was further evaluated. Notably, increasing GABA or inhibiting glutamate levels led to reduced binding of Aβ to pre-labeled plaques to similar extents in APP-PS1 mice while GABA appeared more efficient in Aβ clearance in hypertensive animals than the glutamate inhibitor. Our findings support the modulation of neurotransmitters that influence the glymphatic pathway via distinct mechanisms as a potentially effective therapeutic strategy for clearance of Aβ deposits from the brain.

Abstract P276: (Pro)Renin Receptor-dependent Renal Generation of Aldosterone Contributes to ENaC Activation During Angiotensin II-induced Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Fei Wang ◽  
Kexin Peng ◽  
Xiaohan Lu ◽  
Kevin Yang ◽  
Adam Nau ◽  
...  
Keyword(s):  
Adrenal Glands ◽  
Fold Increase ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Na Transport ◽  
Mineralocorticoid Receptor Antagonist ◽  
Potential Mediator ◽  
Sprague Dawley Rats ◽  
Induced Hypertension ◽  
Local Generation

(Pro)renin receptor (PRR) has emerged as a novel regulator of ENaC under various physiological and pathophysiological conditions including Ang II-induced hypertension. However, the mechanism for ENaC-activating action of PRR remains incompletely understood. The present study attempted to test renal-derived aldosterone (Aldo) as a potential mediator of PRR signaling in the setting of Ang II treatment. In normal Sprague-Dawley rats with intact adrenal glands, a 7-d minipump infusion of Ang II at 100 ng/kg/min induced a 3.2-fold increase in urinary Aldo excretion and a 1.8-fold increase in plasma Aldo, as assessed by ELISA. Following intramedullary delivery of a PRR decoy peptide PRO20 (120 μg/kg/d) (IM PRO20), Ang II-induced increases in urinary Aldo was reduced by 75% without affecting plasma Aldo, in parallel with attenuated hypertension (radiotelemetry-measured MAP on day 7: 132.6 ± 5.8 mmHg in Ang II+IMPRO20 vs. 157.1 ± 6.2 mmHg in Ang II). Following adrenalectomy (ADX), urinary Aldo was decreased from 9.3 ± 1.2 ng/24h to an unbeatable level under basal condition; it was elevated to 0.96 ± 0.05 ng/24h by Ang II and became undetectable again by IM PRO20, as assessed by mass spectrometry. Similar results were obtained by ELISA. In parallel, urinary Na+/K+ ratio in ADX rats was decreased by Ang II infusion and blunted by IM PRO20. Furthermore, Ang II infusion induced a 1.3-fold increase in urinary Aldo excretion and this increase was reduced by 60% in CD PRR KO mice, correlating to the changes in MAP. In cultured mpkCCD cells exposed to 10 nM prorenin, amiloride-sensitive transepithelial Na+ transport, measured by using epithelial volt-ohmmeter, was increased 2.1-fold at 6 h that sustained at 24 h, which was suppressed by 86% following treatment with the mineralocorticoid receptor antagonist eplerenone. Medium Aldo was increased by 2.6-fold following exposure to 10 nM prorenin for 24 h. Overall, these results suggest that activation of PRR results in local generation of Aldo that likely contributes to increased ENaC activity and thus hypertension during Ang II treatment.

Clitoria ternatea L. extract prevents kidney damage by suppressing the Ang II/Nox4/oxidative stress cascade in L-NAME-induced hypertension model of rats

2021 ◽  
pp. 151783
Author(s):  
Benchaporn Saengnak ◽  
Pipatpong Kanla ◽  
Rarinthorn Samrid ◽  
Thewarid Berkban ◽  
Wilaiwan Mothong ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Kidney Damage ◽  
Ang Ii ◽  
Clitoria Ternatea ◽  
Induced Hypertension

Effects of dietary salt changes on renal renin-angiotensin system in rats

2002 ◽  
Vol 283 (5) ◽  
pp. F995-F1002 ◽  
Author(s):  
Catherine Ingert ◽  
Michèle Grima ◽  
Catherine Coquard ◽  
Mariette Barthelmebs ◽  
Jean-Louis Imbs
Keyword(s):  
Renal Cortex ◽  
Salt Content ◽  
Renin Angiotensin System ◽  
Fold Increase ◽  
Kidney Cortex ◽  
Ang Ii ◽  
Dietary Salt ◽  
High Sodium ◽  
Ace Activity ◽  
Wistar Kyoto

Renin (RA) and angiotensin-converting enzyme (ACE) activities and angiotensinogen, ANG I, and ANG II levels were measured in the kidney (cortex and medulla) and plasma of Wistar-Kyoto rats on a low-sodium (LS; 0.025% NaCl; n= 8), normal-sodium (NS; 1% NaCl; n = 7), or high-sodium (HS; 8% NaCl; n = 7) diet for 21 days. RA, ANG I, and ANG II levels increased in a manner inversely related to sodium content of the diet in both plasma and renal tissues. The LS diet resulted in a 16-, 2.8-, and 1.8-fold increase in plasma RA, ANG I, and ANG II levels, respectively, compared with those in HS rats. In the renal cortex and medulla, RA, ANG I, and ANG II levels were also increased by diminution of dietary salt content but, in contrast to plasma, ANG II levels increased much more than RA or ANG I levels [5.4 (cortex)- and 4.7 (medulla)-fold compared with HS rats]. In summary, we demonstrated variations of ANG II levels in the kidney during dietary salt modifications. Our results confirm that RA and ACE activity are not the steps limiting intrarenal ANG II levels. Nevertheless, despite RA and ACE activity differences between renal cortex and medulla, ANG I and ANG II levels are equivalent in these two tissues; these results argue against a compartmentalization of RAS in these two intrarenal areas.

Abstract 442: Endoplasmic Reticulum (ER) Stress in the Subfornical Organ (SFO) Induces Peripheral Inflammation in Angiotensin II (Ang-II)-dependent Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Heinrich E Lob ◽  
Jiunn Song ◽  
Scott D Butler ◽  
Allyn L Mark ◽  
Robin L Davisson
Keyword(s):  
T Cell ◽  
Er Stress ◽  
T Cell Activation ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Fold Increase ◽  
Peripheral Inflammation ◽  
Ang Ii ◽  
Peripheral Vascular ◽  
Control Virus

The SFO is implicated in peripheral T cell activation and the genesis of Ang-II-dependent hypertension. Our recent studies show that ER stress in the SFO is also a key mechanism underlying the development of Ang-II hypertension. Because the ER is closely integrated with initiation of the adaptive immune response, we hypothesized that ER stress in the SFO contributes to peripheral inflammation in Ang-II hypertension. First, 5 days of intracerebroventricular (ICV) infusion of thapsigargin (Tg, 1 ug/day), a chemical ER stress inducer, caused a significant increase in CD3 + T cells in aortas (Tg: 11.9 ± 3.5 x 10 3 cells/aorta vs. Vehicle: 2.2 ± 0.7 x 10 3 cells/aorta , n = 6, p<0.05) and blood (Tg: 9.9 ± 1.8 x 10 4 cells/ mL vs. Vehicle: 2.9 ± 0.6 x 10 4 cells/ mL, n = 6, p<0.05). Furthermore, quantitative real-time PCR of SFO micropunches showed a 15-fold increase of TNF-α, a pro-inflammatory cytokine, a 3-fold increase of CCL5, a T cell attracting chemokine and a 3-fold increase in CD3, a T cell marker, (n = 4, p<0.05). To test the functional role of ER stress in the SFO in peripheral T cell activation, we targeted an adenovirus encoding GRP78 (AdGRP78), a molecular ER stress inhibitor, to this brain region during chronic systemic Ang-II infusion (600 ng/kg/min, 14 days). Our results demonstrate a significant reduction in T cell accumulation in aortas compared to control virus (AdLacZ) treatment (AdGRP78: 0.5 ± 0.07 x 10 4 cells/aorta vs. AdLacZ: 8.7 ± 2.1 x 10 4 cells/aorta, n = 6, p<0.05). These data show that 1) brain ER stress induces inflammation in the SFO and peripheral vascular T cell activation, and 2) ER stress in the SFO is linked to peripheral vascular T cell activation in Ang-II-dependent hypertension. These results suggest that ER stress and inflammation in the SFO induce peripheral vascular T cell activation and inflammation in Ang-II hypertension.

Abstract P231: Inhibition of Mir-762 Prevents and Reverses Ang II Induced Aortic Stiffening

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Aortic Stiffness ◽  
Fold Increase ◽  
Organ Damage ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
New Approach ◽  
Acid Inhibitor ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is linked with striking fibrosis in the aortic adventitia. This leads to aortic stiffening, leading to organ damage. Through a screen of microRNAs (miRNAs) in the aorta, we found that miR-762 is the most upregulated miRNA in Ang II hypertensive mice. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in Ang II-infused mice compared to controls. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762. MiR-762 inhibition normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, miR-762 inhibition in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with 4 wk of Ang II (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + LNA-762 (last 2 wk) [20±1.76 kPa], p<0.0001). Further studies showed that miR-762 inhibition reduced mRNA for several collagens and fibronectin and upregulated collagenases MMP1a, 8 and 13 (Table). Lastly, we found that miR-762 inhibition during Ang II infusion led to a 9.11±1.92 (p=0.007) fold increase in Sprouty1 mRNA, suggesting that miR-762 targets Sprouty1 mRNA. Sprouty1 inhibits the activation of p38-MAPK which is critical in the process of aortic stiffening. Hence, miR-762 modulates aortic stiffening and fibrosis through a Sprouty1-p38-MAPK mechanism. Thus, miR-762 has a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. miR-762 inhibition might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daniel J Fehrenbach ◽  
Meena S Madhur
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Repeated Measures ◽  
Flow Cytometric Analysis ◽  
Coiled Coil ◽  
Ang Ii ◽  
Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

Splenocyte transfer from hypertensive donors eliminates premenopausal female protection from Ang II-induced hypertension

2022 ◽  
Author(s):  
Megan A Sylvester ◽  
Dennis P Pollow ◽  
Caitlin Moffett ◽  
Wendy Nunez ◽  
Jennifer L Uhrlaub ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
Adoptive Transfer ◽  
T Regulatory Cells ◽  
Estrogen Signaling ◽  
Ang Ii ◽  
Regulatory Cells ◽  
Adaptive Immune Cells ◽  
Induced Hypertension ◽  
Rag 1

Premenopausal females are protected from Angiotensin II (Ang II)-induced hypertension following the adoptive transfer of T cells from normotensive donors. For the present study, we hypothesized that the transfer of hypertensive T cells (HT) or splenocytes (HS) from hypertensive donors would eliminate premenopausal protection from hypertension. Premenopausal Rag-1-/- females received either normotensive (NT) or hypertensive cells, three weeks prior to Ang II infusion (14 days, 490 ng/kg/min). Contrary to our hypothesis, no increase in Ang II-induced blood pressure was observed in the NT/Ang or HT/Ang groups. Flow cytometry demonstrated that renal FoxP3+ T regulatory cells were significantly decreased and IHC showed an increase in renal F4/80+ macrophages in HT/Ang, suggesting a shift in the renal inflammatory environment despite no change in blood pressure. Renal mRNA expression of MCP-1, Endothelin-1, GPER-1 were significantly decreased in HT/Ang. The adoptive transfer of hypertensive splenocytes prior to Ang II infusion (HS/Ang) eliminated premenopausal protection from hypertension and significantly decreased splenic FoxP3+ T regulatory cells compared to females receiving normotensive splenocytes (NS/Ang). Expression of MIP-1a/CCL3, a potent macrophage chemokine was elevated in HS/Ang, however no increase in renal macrophage infiltration occurred. Together, these data show that in premenopausal females T cells from hypertensive donors are not sufficient to induce a robust Ang II mediated hypertension, in contrast, transfer of hypertensive splenocytes (consisting of T/B lymphocytes, dendritic cells, macrophages) is sufficient. Further work is needed to understand how innate and adaptive immune cells and estrogen signaling coordinate to cause differential hypertensive outcomes in premenopausal females.

Effect of eprosartan on catecholamines and peripheral haemodynamics in subjects with insulin-induced hypoglycaemia

2005 ◽  
Vol 108 (2) ◽  
pp. 113-119 ◽  
Author(s):  
Marina CHRISTENSEN ◽  
Hans IBSEN ◽  
René WORCK
Keyword(s):  
Body Weight ◽  
Blood Pressure Monitoring ◽  
Animal Experiments ◽  
Plasma Renin ◽  
Fold Increase ◽  
Catecholamine Release ◽  
Repeated Measurements ◽  
Ang Ii ◽  
Double Blind ◽  
Pronounced Increase

ANG II (angiotensin II) facilitates catecholamine release from the adrenal medulla and neuronal NE (noradrenaline) release. Since animal experiments point to specific sympatho-inhibitory properties of the AT1 (ANG II type 1)-receptor blocker EPRO (eprosartan), the primary aim of this study was to clarify if EPRO inhibits sympathetic reactivity in humans as determined by the effect of EPRO on insulin-induced catecholamine release. Sixteen healthy male volunteers were randomized in a double-blind cross-over study to receive a single dose of EPRO (600 mg) compared with placebo, followed by insulin-induced hypoglycaemia [0.15 IU (international unit)/kg of body weight; intravenous bolus] on two study days 1 week apart. From baseline to the end of hypoglycaemia (170 min), the sympatho-adrenal reactivity was mapped by invasive continuous blood pressure monitoring and repeated measurements of FBF (forearm blood flow), arterial and venous concentrations of glucose, catecholamines [EPI (adrenaline) and NE (noradrenaline)], renin, ANG II and aldosterone. EPRO induced an 8–10-fold increase in plasma renin and ANG II concentrations compared with placebo. Plasma glucose decreased equally during placebo and EPRO from baseline 5.9 mmol/l to 1.9 mmol/l and 2.1 mmol/l respectively, inducing a 17-fold increase in arterial EPI concentration at peak. The AUC (area under the curve) during hypoglycaemia for arterial EPI concentrations was 314±48 nmol·min·l−1 in placebo compared with 254±26 nmol·min·l−1 following EPRO treatment (P=0.14). EPRO attenuated the corresponding AUC for the EPI-induced pulse pressure response (4670±219 mmHg·min in EPRO compared with 5004±266 mmHg·min in placebo; P=0.02). Moreover, EPRO caused a less pronounced increase in FBF compared with placebo (402±30 compared with 479±46 ml·100 g−1 of body weight; P=0.04). Musculocutaneous NE release was not affected by EPRO and the AUC for NE release was 51.69±15.5 pmol·min−1·100 g−1 of body weight in placebo compared with 39.35±18.2 pmol·min−1·100 g−1 of body weight after EPRO treatment (P=0.57). In conclusion, EPRO did not significantly inhibit sympathetic reactivity compared with placebo; however, it blunted the haemodynamic responses elicited by the sympatho-adrenal stimulation which only tended to be attenuated by this drug.

scholarly journals A2B adenosine receptor dampens hypoxia-induced vascular leak

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2024-2035 ◽  
Author(s):  
Tobias Eckle ◽  
Marion Faigle ◽  
Almut Grenz ◽  
Stefanie Laucher ◽  
Linda F. Thompson ◽  
...  
Keyword(s):  
Control Point ◽  
Fold Increase ◽  
Vascular Leakage ◽  
Adaptation To Hypoxia ◽  
Vascular Leak ◽  
Extracellular Adenosine ◽  
Fold Reduction ◽  
Complete Reversal

Extracellular adenosine has been implicated in adaptation to hypoxia and previous studies demonstrated a central role in vascular responses. Here, we examined the contribution of individual adenosine receptors (ARs: A1AR/A2AAR/A2BAR/A3AR) to vascular leak induced by hypoxia. Initial profiling studies revealed that siRNA-mediated repression of the A2BAR selectively increased endothelial leak in response to hypoxia in vitro. In parallel, vascular permeability was significantly increased in vascular organs of A2BAR−/−-mice subjected to ambient hypoxia (8% oxygen, 4 hours; eg, lung: 2.1 ± 0.12-fold increase). By contrast, hypoxia-induced vascular leak was not accentuated in A1AR−/−-, A2AAR−/−-, or A3AR−/−-deficient mice, suggesting a degree of specificity for the A2BAR. Further studies in wild type mice revealed that the selective A2BAR antagonist PSB1115 resulted in profound increases in hypoxia-associated vascular leakage while A2BAR agonist (BAY60-6583 [2-[6-amino-3,5-dicyano-4-[4-(cyclopropylmethoxy)-. phenyl]pyridin-2-ylsulfanyl]acetamide]) treatment was associated with almost complete reversal of hypoxia-induced vascular leakage (eg, lung: 2.0 ± 0.21-fold reduction). Studies in bone marrow chimeric A2BAR mice suggested a predominant role of vascular A2BARs in this response, while hypoxia-associated increases in tissue neutrophils were, at least in part, mediated by A2BAR expressing hematopoietic cells. Taken together, these studies provide pharmacologic and genetic evidence for vascular A2BAR signaling as central control point of hypoxia-associated vascular leak.

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