Hypertension and mineralocorticoid receptor activation cause cerebral parenchymal arteriole remodeling; this can limit cerebral perfusion and contribute to cognitive dysfunction. We utilized a mouse model of angiotensin II-induced hypertension to test the hypothesis that mineralocorticoid receptor activation impairs both TRPV4-mediated dilation of cerebral parenchymal arterioles and cognitive function. 16-18-week-old male C57bl/6 mice were treated with angiotensin II (800ng/kg/min) ± the mineralocorticoid receptor antagonist, eplerenone (100mg/kg/day) for 4 weeks; sham mice served as controls. Data are presented as mean ± SEM; n=5-14 per group. Eplerenone prevented the increased parenchymal arteriole myogenic tone and impaired carbachol-induced (10-10mol/L) dilation observed during hypertension. The carbachol-induced dilation was endothelium-derived hyperpolarization mediated because it could not be blocked by L-NAME (10mol/L) and indomethacin (10mol/L). We used GSK2193874 (10mol/L) to confirm that in all groups this dilation was dependent on TRPV4 activation. Dilation in response to the TRPV4 agonist GSK1016790A (10-10mol/L) was also reduced in the hypertensive mice and this defect was corrected by eplerenone. In the hypertensive and eplerenone treated animals, TRPV4 inhibition reduced myogenic tone, an effect that was not observed in arterioles from control animals. Eplerenone treatment also improved cognitive function and reduced microglia density in the hypertensive mice. These data suggest that the mineralocorticoid receptor is a potential therapeutic target to improve cerebrovascular function and cognition during hypertension.

Artery remodeling, described as a change in artery structure, may be responsible for the increased risk of cardiovascular disease with aging. Although the risk for stroke is known to increase with age, relatively young animals have been used in most stroke studies. Therefore, more information is needed on how aging alters the biomechanical properties of cerebral arteries. Posterior cerebral arteries (PCAs) and parenchymal arterioles (PAs) are important in controlling brain perfusion. We hypothesized that aged (22-24 mo old) C57bl/6 mice would have stiffer PCAs and PAs than young (3-5 mo old) mice. The biomechanical properties of the PCAs and PAs were assessed by pressure myography. Data are presented as means ± SE of young vs. old. In the PCA, older mice had increased outer (155.6 ± 3.2 vs. 169.9 ± 3.2 μm) and lumen (116.4 ± 3.6 vs. 137.1 ± 4.7 μm) diameters. Wall stress (375.6 ± 35.4 vs. 504.7 ± 60.0 dyn/cm(2)) and artery stiffness (β-coefficient: 5.2 ± 0.3 vs. 7.6 ± 0.9) were also increased. However, wall strain (0.8 ± 0.1 vs. 0.6 ± 0.1) was reduced with age. In the PAs from old mice, wall thickness (3.9 ± 0.3 vs. 5.1 ± 0.2 μm) and area (591.1 ± 95.4 vs. 852.8 ± 100 μm(2)) were increased while stress (758.1 ± 100.0 vs. 587.2 ± 35.1 dyn/cm(2)) was reduced. Aging also increased mean arterial and pulse pressures. We conclude that age-associated remodeling occurs in large cerebral arteries and arterioles and may increase the risk of cerebrovascular disease.

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.

Hypertension is a leading risk factor for vascular cognitive impairment and is strongly associated with carotid artery stenosis. In normotensive rats, chronic cerebral hypoperfusion induced by bilateral common carotid artery stenosis (BCAS) leads to cognitive impairment that is associated with impaired endothelium-dependent dilation in parenchymal arterioles (PAs). The aim of this study was to assess the effects of BCAS on PA function and structure in stroke-prone spontaneously hypertensive rats, a model of human essential hypertension. Understanding the effects of hypoperfusion on PAs in a hypertensive model could lead to the identification of therapeutic targets for cognitive decline in a model that reflects the at-risk population. We hypothesized that BCAS would impair endothelium-dependent dilation in PAs and induce artery remodeling compared with sham rats. PAs from BCAS rats had endothelial dysfunction, as assessed using pressure myography. Inhibition of nitric oxide and prostaglandin production had no effect on PA dilation in sham or BCAS rats. Surprisingly, inhibition of epoxyeicosatrienoic acid production increased dilation in PAs from BCAS rats but not from sham rats. Similar results were observed in the presence of inhibitors for all three dilatory pathways, suggesting that epoxygenase inhibition may have restored a nitric oxide/prostaglandin-independent dilatory pathway in PAs from BCAS rats. PAs from BCAS rats underwent remodeling with a reduced wall thickness. These data suggest that marked endothelial dysfunction in PAs from stroke-prone spontaneously hypertensive rats with BCAS may be associated with the development of vascular cognitive impairment. NEW & NOTEWORTHY The present study assessed the structure and function of parenchymal arterioles in a model of chronic cerebral hypoperfusion and hypertension, both of which are risk factors for cognitive impairment. We observed that impaired dilation and artery remodeling in parenchymal arterioles and abolished cerebrovascular reserve capacity may mediate cognitive deficits.

Objective Hypertension‐associated PA dysfunction reduces cerebral perfusion and impairs cognition. This is associated with impaired TRPV4‐mediated PA dilation; therefore, we tested the hypothesis that TRPV4 channels are important regulators of cerebral perfusion, PA structure and dilation, and cognition. Methods Ten‐ to twelve‐month‐old male TRPV4 knockout (WKY‐Trpv4em4Mcwi) and age‐matched control WKY rats were studied. Cerebral perfusion was measured by MRI with arterial spin labeling. PA structure and function were assessed using pressure myography and cognitive function using the novel object recognition test. Results Cerebral perfusion was reduced in the WKY‐Trpv4em4Mcwi rats. This was not a result of PA remodeling because TRPV4 deletion did not change PA structure. TRPV4 deletion did not change PA myogenic tone development, but PAs from the WKY‐Trpv4em4Mcwi rats had severely blunted endothelium‐dependent dilation. The WKY‐Trpv4em4Mcwi rats had impaired cognitive function and exhibited depressive‐like behavior. The WKY‐Trpv4em4Mcwi rats also had increased microglia activation, and increased mRNA expression of GFAP and tumor necrosis factor alpha suggesting increased inflammation. Conclusion Our data indicate that TRPV4 channels play a critical role in cerebral perfusion, PA dilation, cognition, and inflammation. Impaired TRPV4 function in diseases such as hypertension may increase the risk of the development of vascular dementia.

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In a model of secondary hypertension, mineralocorticoid receptor (MR) antagonism during the development of hypertension prevents the impairment of transient receptor potential vanilloid 4 (TRPV4) activation in parenchymal arterioles (PAs) and cognitive impairment. However, it is unknown whether MR antagonism can improve these impairments when treatment begins after the onset of essential hypertension. We tested the hypothesis that MR activation in stroke-prone spontaneously hypertensive rats (SHRSP) leads to impaired TRPV4-mediated dilation in PAs that is associated with cognitive dysfunction and neuroinflammation.Methods: 20-22-week-old male SHRSP AE eplerenone (EPL; 100 mg/kg daily for 4 weeks) were compared to normotensive SpragueÀDawley (SD) rats. Pressure myography was used to assess PA function. Cognition was tested using Y-maze. Neuroinflammation was assessed using immunofluorescence and qRT-PCR.Results: Carbachol-mediated endothelium-dependent dilation was impaired in SHRSP, and MR antagonism improved this without affecting myogenic tone. Dilation to TRPV4 agonist GSK1016790A was impaired in SHRSP, and ELP treatment restored this. Intermediate conductance potassium channel (IK Ca )/small conductance potassium channel (SK Ca )-mediated dilation was impaired by hypertension and unaffected by EPL treatment. TRPV4 and IK Ca /SK Ca channel mRNA expression were reduced in PAs from hypertensive rats, and EPL did not improve this. Impairments in PA dilation in SHRSP were associated with cognitive decline, microglial activation, reactive astrogliosis, and neuroinflammation; cognitive and inflammatory changes were improved with MR blockade.Conclusions: These data advance our understanding of the effects of hypertension on cerebral arterioles using a clinically relevant model and treatment paradigm. Our studies suggest TRPV4 and the MR are potential therapeutic targets to improve cerebrovascular function and cognition during hypertension.

Mineralocorticoid receptor (MR) activation causes cerebral parenchymal arteriole (PA) remodeling, impaired endothelium‐dependent dilation and cognitive dysfunction in hypertension. We used a mouse model of angiotensin II (AngII)‐induced hypertension to test the hypothesis that endothelial cell mineralocorticoid receptor (EC‐MR) activation impairs parenchymal arteriole (PA) transient receptor potential vanilloid 4 (TRPV4)‐mediated dilation and cognitive function. 16–18‐week‐old MR‐intact and endothelial mineralocorticoid receptor knockout (ECMRKO) mice were treated with AngII (800ng/kg/min) for 4 weeks; shams served as controls. Data are presented as means ± SEM; n=5–14 per group. EC‐MR deletion under control conditions did result in vascular changes. EC‐MR deletion prevented the impaired PA carbachol (CCh)‐mediated dilation in hypertension but not the increased myogenic tone. The TRPV4 inhibitor, GSK2193874 (10−7M) was used to confirm the importance of TRPV4 activation in CCh‐mediated dilation. TRPV4 inhibition blunted the CCh‐mediated dilation in all groups. Dilation in response to the TRPV4 agonist GSK1016790A (10−9–10−5mol/L) and IKCa/SKCa agonist NS309 (10−9–10−5mol/L) were also reduced in the hypertensive mice and this was corrected by EC‐MR deletion. Hypertensive mice had impaired cognitive function, but this was not corrected by EC‐MR deletion. Plasma protein oxidation was not altered by EC‐MR deletion or AngII treatment. The mRNA expression of markers for neuronal support and synapse proteins, synaptophysin (SYP), brain derived neurotrophic factor (BDNF) were not altered by AngII. However, the mRNA expression of doublecortin (DC) was reduced by AngII and EC‐MR deletion prevented this. Our data shows that EC‐MR signaling mediates PA endothelium‐dependent dilation but not cognitive function and suggests that the MR is a potential therapeutic target to improve cerebrovascular function during hypertension.Support or Funding InformationR01‐HL‐137694‐01 and PO1‐HL‐070687 to WF Jackson and AMDorrance 5T32GM092715‐04 and F31NS090866 ‐ J.M. Diaz‐OteroR01‐HL095590 ‐ I.Z. Jaffe. J.M.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.