Plasticity of cerebral microvascular structure and mechanics during hypertension and following recovery of arterial pressure.

Changes in vascular structure contribute to vascular events and loss of brain health. We examined changes in cerebral arterioles at the onset of hypertension and the hypothesis that alterations during hypertension would recover with the return of mean arterial pressure (MAP) to normal. MAP was measured with radiotelemetry in awake male C57BL/6J mice at baseline and during infusion of vehicle or angiotensin II (ANG II, 1.

Deficiency of superoxide dismutase promotes cerebral vascular hypertrophy and vascular dysfunction in hyperhomocysteinemia.

There is an emerging consensus that hyperhomocysteinemia is an independent risk factor for cerebral vascular disease and that homocysteine-lowering therapy protects from ischemic stroke. However, the mechanisms by which hyperhomocysteinemia produces abnormalities of cerebral vascular structure and function remain largely undefined. Our objective in this study was to define the mechanistic role of superoxide in hyperhomocysteinemia-induced cerebral vascular dysfunction and hypertrophy.

Roles of Caveolin-1 in Angiotensin II-Induced Hypertrophy and Inward Remodeling of Cerebral Pial Arterioles.

Angiotensin II (Ang II) is a major determinant of inward remodeling and hypertrophy in pial arterioles that may have an important role in stroke during chronic hypertension. Previously, we found that epidermal growth factor receptor is critical in Ang II-mediated hypertrophy that may involve caveolin-1 (Cav-1). In this study, we examined the effects of Cav-1 and matrix metalloproteinase-9 (MMP9) on Ang II-mediated structural changes in pial arterioles.

Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice.

Objective: We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice.

Approach And Results: At 1.

Epidermal growth factor receptor is critical for angiotensin II-mediated hypertrophy in cerebral arterioles.

Angiotensin II (Ang II) is a major determinant of vascular remodeling in the cerebral circulation during chronic hypertension, which is an important risk factor for stroke. We examined the molecular mechanism of Ang II-mediated cerebrovascular remodeling that involves the epidermal growth factor receptor (EGFR) pathway. Mutant EGFR mice (waved-2), their heterozygous control (wild-type [WT]), and C57BL/6J mice were infused with Ang II (1000 ng kg(-1) min(-1)) or saline via osmotic minipumps for 28 days (n=8 per group).

Nox2 deficiency prevents hypertension-induced vascular dysfunction and hypertrophy in cerebral arterioles.

Oxidative stress is involved in many hypertension-related vascular diseases in the brain, including stroke and dementia. Thus, we examined the role of genetic deficiency of NADPH oxidase subunit Nox2 in the function and structure of cerebral arterioles during hypertension. Arterial pressure was increased in right-sided cerebral arterioles with transverse aortic banding for 4 weeks in 8-week-old wild-type (WT) and Nox2-deficient (-/y) mice.

Overexpression of dimethylarginine dimethylaminohydrolase protects against cerebral vascular effects of hyperhomocysteinemia.

Rationale: Hyperhomocysteinemia is a cardiovascular risk factor that is associated with elevation of the nitric oxide synthase inhibitor asymmetrical dimethylarginine (ADMA).

Objective: Using mice transgenic for overexpression of the ADMA-hydrolyzing enzyme dimethylarginine dimethylaminohydrolase-1 (DDAH1), we tested the hypothesis that overexpression of DDAH1 protects from adverse structural and functional changes in cerebral arterioles in hyperhomocysteinemia.

Methods And Results: Hyperhomocysteinemia was induced in DDAH1 transgenic (DDAH1 Tg) mice and wild-type littermates using a high methionine/low folate (HM/LF) diet.

Cerebral arteriolar thromboembolism in idiopathic hypereosinophilic syndrome.

Objective: To describe imaging findings as well as postmortem brain and cardiac pathology in a patient with fulminant idiopathic hypereosinophilic syndrome.

Design: Case report.

Setting: University hospital.

Interference with PPAR gamma function in smooth muscle causes vascular dysfunction and hypertension.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand-activated transcription factor that plays a critical role in metabolism. Thiazolidinediones, high-affinity PPARgamma ligands used clinically to treat type II diabetes, have been reported to lower blood pressure and provide other cardiovascular benefits. Some mutations in PPARgamma (PPARG) cause type II diabetes and severe hypertension.

Oxidative stress through activation of NAD(P)H oxidase in hypertensive mice with spontaneous intracranial hemorrhage.

We have developed an experimental model of spontaneous intracranial hemorrhage (ICH) in transgenic mice expressing human renin and human angiotensinogen (R+/A+) treated with high-salt diet and N(omega)-nitro-L-arginine methyl ester (L-NAME). We investigated whether oxidative stress is associated with spontaneous ICH in R+/A+ mice. R+/A+ mice on high-salt diet and L-NAME presented neurologic signs 57+/-13 (mean+/-s.

Interference with PPARgamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling.

The transcription factor PPARgamma is expressed in endothelium and vascular muscle where it may exert antiinflammatory and antioxidant effects. We tested the hypothesis that PPARgamma plays a protective role in the vasculature by examining vascular structure and function in heterozygous knockin mice expressing the P465L dominant negative mutation in PPARgamma (L/+). In L/+ aorta, responses to the endothelium-dependent agonist acetylcholine (ACh) were not affected, but there was an increase in contraction to serotonin, PGF(2alpha), and endothelin-1.

Hypertrophy of cerebral arterioles in mice deficient in expression of the gene for CuZn superoxide dismutase.

Background And Purpose: Reactive oxygen species are believed to be an important determinant of vascular growth. We examined effects of genetic deficiency of copper-zinc superoxide dismutase (CuZnSOD; SOD1) on structure and function of cerebral arterioles.

Methods: Systemic arterial pressure (SAP) and cross-sectional area of the vessel wall (CSA) and superoxide (O2-) levels (relative fluorescence of ethidium [ETH]) were examined in maximally dilated cerebral arterioles in mice with targeted disruption of one (+/-) or both (-/-) genes encoding CuZnSOD.

Spontaneous stroke in a genetic model of hypertension in mice.

Background And Purpose: Hypertension is the most common risk factor for hemorrhagic stroke. An experimental model of stroke, the stroke-prone spontaneously hypertensive rat (SHRSP), which has been enormously useful in studies of cerebral circulation, has been used in >1000 papers. However, SHRSP usually have an ischemic or less commonly hemorrhagic stroke in the cortex, not in the brain stem, cerebellum, or basal ganglia, as in patients with hypertension.

Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes.

Background And Purpose: Although the incidence of type II diabetes is increasing, very little is known regarding vascular responses in the cerebral circulation in this disease. The goals of this study were to examine the role of superoxide in impaired endothelium-dependent responses and to examine the influence of Rho-kinase on vascular tone in the cerebral microcirculation in type II diabetes.

Methods: Diameter of cerebral arterioles (29+/-1 microm; mean+/-SE) was measured in vivo using a cranial window in anesthetized db/db and control mice.

Structure of cerebral arterioles in mice deficient in expression of the gene for endothelial nitric oxide synthase.

We examined effects of pharmacological inhibition of nitric oxide synthase (NOS) and genetic deficiency of the endothelial isoform of NOS (eNOS) on structure and mechanics of cerebral arterioles. We measured pressure, diameter, and cross-sectional area (CSA) of the vessel wall (histologically) in maximally dilated cerebral arterioles in mice that were untreated or treated for 3 months with the NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME; 10 mg/kg per day in drinking water). Treatment with L-NAME increased systemic arterial mean pressure (SAP; 143+/-4 versus 121+/-4 mm Hg, P<0.

Effects of chronic nitric oxide synthase inhibition on cerebral arterioles in Wistar-Kyoto rats.

Objective: Cerebral arterioles in stroke-prone spontaneously hypertensive rats (SHRSP), but not in Sprague-Dawley rats with hypertension induced by nitric oxide (NO) synthase inhibition, undergo inward remodeling. The goal of this study was to determine whether development of vascular inward remodeling may depend on genetic factors.

Design: We examined effects of NO synthase inhibition on the structure of cerebral arterioles in Wistar-Kyoto rats (WKY), a rat strain genetically distinct from Sprague-Dawley.

Effects of indapamide, a thiazide-like diuretic, on structure of cerebral arterioles in hypertensive rats.

We examined the effects of indapamide, a thiazide-like diuretic, on cerebral arterioles in spontaneously hypertensive rats (SHR). The structure and mechanics of cerebral arterioles were examined in untreated Wistar Kyoto rats (WKY) and SHR that were untreated or treated for 3 months with a low (1 mg/kg per day) or a high (10 mg/kg per day) dose of indapamide. We measured pressure, diameter, and cross-sectional area of the vessel wall (CSA) in maximally-dilated (EDTA) cerebral arterioles.

Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen.

We examined the hypothesis that the renin-angiotensin system plays an important role in vascular remodeling (defined as reduced external diameter) during chronic hypertension. We measured pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in transgenic mice that overexpress both human renin and human angiotensinogen and in spontaneously hypertensive mice, a model of chronic hypertension that is thought to develop independently of the renin-angiotensin system. Systemic arterial pressure under conscious conditions was increased by similar amounts in transgenically hypertensive mice (153+/-6 versus 117+/-4 mm Hg in controls; mean+/-SE, P<0.

Structure of cerebral arterioles in cystathionine beta-synthase-deficient mice.

We examined effects of hyperhomocysteinemia on structure and mechanics of cerebral arterioles. We measured plasma total homocysteine (tHcy) and pressure, diameter, and cross-sectional area of the vessel wall in maximally dilated cerebral arterioles in heterozygous cystathionine beta-synthase-deficient (CBS(+/-)) mice and wild-type (CBS(+/+)) littermates that were provided with drinking water that was unsupplemented (control diet) or supplemented with 0.5% L-methionine (high-methionine diet).

Superoxide contributes to vascular dysfunction in mice that express human renin and angiotensinogen.

This study examined vascular function and the role of superoxide in mice that chronically express human renin (R+) and human angiotensinogen (A+). Responses of aortas from R+/A+ mice and from their normotensive littermates (RA- mice) were examined in vitro. Endothelium-dependent relaxation to acetylcholine was impaired in vessels from R+/A+ mice (e.