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Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

ABSTRACT: The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrapolated to the brain. The parenchymal arterioles determine cerebrovascular resistance. Determining the effects of hypertension and MR signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial MR signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin II (AngII) hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell-specific MR knockout mice and their appropriate controls using pressure myography. AngII increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and MR-intact littermates. Endothelial cell MR deletion improved cerebral perfusion in AngII-treated mice. AngII hypertension resulted in inward hypotrophic remodeling; this was prevented by MR antagonism and endothelial MR deletion. Our studies suggest that endothelial cell MR mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. AngII-induced inward remodeling of cerebral arteries and arterioles was associated with a reduction in cerebral perfusion that could worsen the outcome of stroke or contribute to vascular dementia.

SUBMITTER: Diaz-Otero JM

PROVIDER: S-EPMC5680120 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

Diaz-Otero Janice M JM Fisher Courtney C Downs Kelsey K Moss M Elizabeth ME Jaffe Iris Z IZ Jackson William F WF Dorrance Anne M AM

Hypertension (Dallas, Tex. : 1979) 20171003 6

The brain is highly susceptible to injury caused by hypertension because the increased blood pressure causes artery remodeling that can limit cerebral perfusion. Mineralocorticoid receptor (MR) antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial MR mediates hypertension-induced vascular injury, but cerebral and peripheral arteries are anatomically distinct; thus, these findings cannot be extrap ...[more]

PMID: 28974571

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Project description:SignificanceVascular mural cells, defined as smooth muscle cells (SMCs) and pericytes, influence brain microcirculation, but how they contribute is not fully understood. Most approaches used to investigate pericyte and capillary interactions include ex vivo retinal/slice preparations or in vivo two-photon microscopy. However, neither method adequately captures mural cell behavior without interfering neuronal tissue. Thus, there is a need to isolate vessels with their respective mural cells to study functional and pathological changes.AimThe aim of our work was to implement an ex vivo method that recapitulates vessel dynamics in the brain.ApproachExpanding upon our established ex vivo capillary-parenchymal arteriole (CaPA) preparation, we isolated and pressurized arteriole-capillary branches. Using Alexa Fluor™ 633 Hydrazide, we distinguished arterioles (containing elastin) versus capillaries (lacking elastin). In addition, our transgenic SMMHC-GCaMP6f mice allowed for us to visualize mural cell morphology and Ca2+ signals. Lastly, isolated microvasculature was cultured in DMEM media (up to 72 h), mounted, and pressurized using our CaPA preparation.ResultsU46619 induced a decrease in capillary lumen diameter using both a bath perfusion and local application. In addition, U46619 increased Ca2+ signaling both globally and locally in contractile pericytes. In our SMMHC-GCaMP6f mice, we saw that thin strand pericytes had sparse processes while contractile pericytes had long, thick processes that wrapped around the lumen of the capillary. Fresh and cultured pericytes constricted in response to U46619 to the same level, and upstream arteriolar dilation induced by capillary stimulation with 10 mM K+ remained unchanged by culture conditions adding another application of longer treatment to our approach.ConclusionOur ex vivo CaPA methodology facilitates observation of arteriolar SMC and pericyte dynamic changes in real-time without environmental factors. This method will help to better understand how mural cells differ based on microvasculature location.

Project description:Introduction: Endovascular therapy (EVT) is established as first-line treatment for acute ischemic stroke (AIS) due to large vessel occlusion (LVO) in the anterior circulation. For basilar artery occlusion, recent randomized clinical trials demonstrated not only equipoise but also advantages for EVT under particular circumstances. It remains unclear whether EVT offers an advantage over best medical management (BMM) including thrombolysis (IVT) in isolated occlusion of the proximal posterior cerebral artery (PCAO). Methods: Patients with AIS due to PCAO proven by CT or MR angiography were retrospectively identified from local databases at four comprehensive stroke centers in Germany, USA, and Taiwan between 2012 and 2020. Demographic and clinical data were collected, and imaging characteristics including pretherapeutic, interventional, and follow-up imaging were reviewed locally at each center. Patients were grouped according to therapy, i.e., BMM including IVT alone vs. BMM and EVT. Efficacy endpoints were early neurological improvement (ENI) after 24 h or at discharge, good outcome (modified Rankin scale 0-2) after 3 months, as well as hemorrhagic complications and in-house deaths as safety endpoints. Results: We included 130 patients of whom 23 (17.7%) received EVT. EVT patients had more proximal occlusions (69.9 vs. 43%, p = 0.023) and had a better premorbid function [premorbid mRS, 0 (0-4) vs. 1 (0-3), p < 0.01] when compared to BMM patients. IVT showed a trend toward being less performed in the EVT group (21.7 vs. 41.1%, p = 0.1), while other baseline parameters were balanced. Successful reperfusion was achieved in 52% of EVT patients. ENI was more frequent in the EVT group (61 vs. 35.5%, p = 0.034). Good outcome at 90 days and safety endpoints did not differ. In a bivariate analysis, ENI was independently predicted by the use of EVT (OR, 2.76; CI, 1.055-7.04) and the baseline National Institutes of Health Stroke Scale (NIHSS) (OR, 1.082; CI, 1.027-1.141 per point increase). Discussion: EVT in isolated PCAO appears safe and feasible. Positive effects on clinical outcome are primarily on ENI but also depend on the initial stroke severity. Further prospective or randomized studies are needed to better describe the potential long-term clinical benefits of EVT for PCAO as compared with best medical management.

Dataset Information

Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

Publications

Endothelial Mineralocorticoid Receptor Mediates Parenchymal Arteriole and Posterior Cerebral Artery Remodeling During Angiotensin II-Induced Hypertension.

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