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 antagonism prevents hypertensive cerebral artery remodeling, but the vascular cell types involved have not been defined. In the periphery, the endothelial mineralocorticoid receptor 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 mineralocorticoid receptor signaling on these arterioles could lead to a better understanding of cerebral small vessel disease. We hypothesized that endothelial mineralocorticoid receptor signaling mediates inward cerebral artery remodeling and reduced cerebral perfusion during angiotensin-II hypertension. The biomechanics of the parenchymal arterioles and posterior cerebral arteries were studied in male C57Bl/6 and endothelial cell specific mineralocorticoid receptor knockout mice and their appropriate controls using pressure myography. Angiotensin-II increased plasma aldosterone and decreased cerebral perfusion in C57Bl/6 and mineralocorticoid receptor-intact littermates. Endothelial cell mineralocorticoid receptor deletion improved cerebral perfusion in angiotensin-II treated mice. Angiotensin-II hypertension resulted in inward hypotrophic remodeling; this was prevented by mineralocorticoid receptor antagonism and endothelial mineralocorticoid receptor deletion. Our studies suggest that endothelial cell mineralocorticoid receptor mediates hypertensive remodeling in the cerebral microcirculation and large pial arteries. Angiotensin II-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.

Augmented astrocyte microdomain Ca2+ dynamics and parenchymal arteriole tone in angiotensin II‐infused hypertensive mice

“…Several significant findings were revealed from hypertensive mice. First, consistent with previous studies in various models of hypertension (Chan et al, ; De Silva et al, ; Diaz‐Otero et al, ; Pires et al, ; Sweet et al, ), PA from hypertensive mice show enhanced myogenic tone. Second, both an increase in spontaneous and myogenic‐evoked astrocyte MD Ca 2+ events were observed.…”

“…Importantly, we demonstrated that during myogenic (pressure‐evoked) constrictions, astrocytes respond with an increase in Ca 2+ resulting in the release of vasoactive signals which aid in the maintenance of parenchymal arteriole (PA) tone (Kim et al, ). Chronic hypertension causes arteriole remodeling (Baumbach & Heistad, ; Hart, Heistad, & Brody, ; Intengan & Schiffrin, ) and increases in vascular tone (Chan, Sweet, & Cipolla, ; De Silva, Kinzenbaw, Modrick, Reinhardt, & Faraci, ; Diaz‐Otero et al, ; Iddings, Kim, Zhou, Higashimori, & Filosa, ; Pires, Jackson, & Dorrance, ; Sweet, Chan, & Cipolla, ). In addition, chronic hypertension evokes a rightward shift of the CA curve (Paulson, Waldemar, Schmidt, & Strandgaard, ; Saavedra, Benicky, & Zhou, ) protecting the brain from high pressures.…”

Transient receptor potential vanilloid 4 channels are important regulators of parenchymal arteriole dilation and cognitive function

“…A servo‐null system was used to pressurize the arterioles, and a leak test was performed prior to each experiment. Arterioles were pressurized to 60 mm Hg until the development of stable myogenic tone (% tone = [1−(active lumen diameter/passive lumen diameter)] × 100. The diameter of the arterioles was recorded using MyoView 2.0 software (Danish Myo Technology, Aarhus, Denmark).…”

“…Blood pressure was measured in conscious rats by tail-cuff plethysmography using a RTBP1001 tail-cuff blood pressure system (Kent Scientific, Torrington, CT) as described previously. 5,21,22…”

“…We have previously shown that aging is associated with remodeling of PAs. 4 Also, that hypertension causes inward hypotrophic remodeling 5 and impairs endothelium-dependent dilation of PAs; these changes were associated with reduced cerebral perfusion and impaired cognitive function. 6 We are interested in the role of the TRPV4 channel in cSVD and vascular cognitive impairment.…”