Chronic hypertension impairs dilatation of cerebral arterioles. Impairment of dilatation generally has been attributed to hypertrophy of the vessel wall with encroachment on the vascular lumen. In this study, we tested the hypothesis that a reduction in external diameter may contribute to encroachment on the vascular lumen during chronic hypertension. We examined 10-12-month-old, anesthetized Wistar-Kyoto (WKY) rats and stroke-prone spontaneously hypertensive rats (SHRSP). External diameter, stress, and strain of pial arterioles were calculated from measurements of pial arteriolar pressure (servo null), diameter, and crosssectional area of the arteriolar wall. During maximal dilatation produced with ethylenediaminetetraacetic acid, cross-sectional area of the arteriolar wall was greater in SHRSP than in WKY rats (2,038±57 vs. 1,456±61 fim 2 , p<0.05). External, as well as internal, diameter was less in SHRSP than in WKY rats (101+3 and 88±3 /tm in SHRSP vs. 111±3 and 102±3 fim in WKY rats for external and internal diameter, respectively, p<0.05). Reduction in external diameter accounted for 76% of encroachment on the lumen in SHRSP, and hypertrophy per se accounted for only 24%. Distensibility of deactivated pial arterioles was increased in SHRSP. These findings suggest that reduction in external diameter plays an important role in impairment of maximal dilatation of cerebral arterioles in SHRSP, and reduction in vascular diameter in SHRSP cannot be accounted for by altered distensibility. We propose that, during chronic hypertension, cerebral arterioles undergo structural remodeling that results in a smaller external diameter and encroachment on the vascular lumen. Reduction in external diameter appears to account for most of the impairment of cerebral vasodilatation that occurs in chronic hypertension. (Hypertension 1989;13:968-972) C hronic hypertension impairs responses of cerebral blood vessels to a variety of dilator stimuli. Increases in cerebral blood flow during seizures and hypercapnia are less in hypertensive rats than normotensive rats.12 During maximal' dilatation, internal diameter of large cerebral arteries 3 -5 and cerebral arterioles 6 is smaller in spontaneously hypertensive rats (SHR) and strokeprone spontaneously hypertensive rats (SHRSP) than in normotensive Wistar-Kyoto (WKY) rats. This manuscript from the University of Iowa was sent to Carlos M. Ferrario, Guest Editor, for review by expert referees, for editorial decision, and for final disposition.Address for reprints: Gary L. Baumbach, MD, Department of Pathology, 120 Medical Laboratories, University of Iowa, Iowa City, IA 52242. Impairment of vasodilator capacity by chronic hypertension generally is attributed to hypertrophy of the vessel wall with encroachment on the lumen and reduction in internal diameter of the vessels. Hypertrophy during chronic hypertension has been demonstrated in cerebral arterioles.6 -8 It is not clear, however, whether the magnitude of hypertrophy is sufficient to account for the reduction in diameter of cereb...

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. Here we tested the hypothesis that PPARgamma in vascular muscle plays a role in the regulation of vascular tone and blood pressure. Transgenic mice expressing dominant-negative mutations in PPARgamma under the control of a smooth-muscle-specific promoter exhibit a loss of responsiveness to nitric oxide and striking alterations in contractility in the aorta, hypertrophy and inward remodeling in the cerebral microcirculation, and systolic hypertension. These results identify PPARgamma as pivotal in vascular muscle as a regulator of vascular structure, vascular function, and blood pressure, potentially explaining some of the cardioprotective effects of thiazolidinediones.

Chronic hypertension is associated with hypertrophy of cerebral blood vessels. Previous studies of the mechanical properties of cerebral vessels in chronic hypertension have examined large cerebral arteries. The goals of this study were first to develop a method to examine vascular mechanics of cerebral arterioles in vivo and second to determine whether the stiffness of cerebral arterioles is altered in the presence of chronic hypertension. We calculated circumferential stress and strain of pial arterioles in age-matched, anesthetized stroke-prone spontaneously hypertensive rats (SHRSP) and in Wistar Kyoto rats (WKY) from measurements of pial arteriolar pressure, inner diameter, and wall thickness. Pial arteriolar pressure was measured with a servonull system. Smooth muscle of pial arterioles was deactivated with ethylenediaminetetraacetic acid (EDTA), and pressure-diameter relations were examined during step-wise reductions in pressure. Prior to deactivation of smooth muscle in 3-4-month-old rats, pial arteriolar pressure was greater in SHRSP than in WKY (110 +/- 4 versus 75 +/- 2 mm Hg [mean +/- SE]; p less than 0.05). Pial arteriolar diameter, which was measured at prevailing levels of pial arteriolar pressure, was less in SHRSP than in WKY (52 +/- 5 versus 63 +/- 3 microns; p less than 0.05). Following deactivation of smooth muscle, diameter of pial arterioles at 70 mm Hg of pial arteriolar pressure was similar in the two groups: 104 +/- 6 microns in SHRSP and 109 +/- 3 microns in WKY (p greater than 0.05). Wall thickness was 4.5 +/- 0.2 microns in SHRSP and 4.1 +/- 0.1 microns in WKY (p greater than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

The purpose of this study was to determine directly segmental cerebral vascular resistance during sympathetic stimulation and changes in arterial pressure. We measured pressure in pial arteries in anesthetized rabbits and cats with a servo-null pressure-measuring device. Cerebral blood flow was measured with microspheres. Using these measurements we calculated large artery resistance and small vessel resistance. Under control conditions, large artery resistance accounted for approximately 40% of total cerebral vascular resistance. Sympathetic stimulation increased large artery resistance and reduced pial artery pressure. Cerebral blood flow and total cerebral vascular resistance did not change significantly. To examine constrictor responses of small cerebral vessels, we raised cerebral perfusion pressure by obstructing the descending aorta. During increases in arterial pressure from 70 to 110 mm Hg, large artery resistance tended to increase and small vessel resistance increased significantly. We conclude that, although sympathetic stimulation has little effect on total cerebral vascular resistance under normal conditions, it has important effects on segmental vascular resistance and cerebral microvascular pressure, and that sympathetic stimulation and increases in systemic arterial pressure within the physiological range have markedly different effects on segmental resistance; i.e., sympathetic stimulation produces constriction only in large arteries, and increases in systemic arterial pressure within the physiological range produce constriction primarily in small vessels.

Abstract-The transcription factor PPAR␥ is expressed in endothelium and vascular muscle where it may exert antiinflammatory and antioxidant effects. We tested the hypothesis that PPAR␥ plays a protective role in the vasculature by examining vascular structure and function in heterozygous knockin mice expressing the P465L dominant negative mutation in PPAR␥ (L/ϩ). In L/ϩ aorta, responses to the endothelium-dependent agonist acetylcholine (ACh) were not affected, but there was an increase in contraction to serotonin, PGF 2␣ , and endothelin-1. In cerebral blood vessels both in vitro and in vivo, ACh produced dilation that was markedly impaired in L/ϩ mice. Superoxide levels were elevated in cerebral arterioles from L/ϩ mice and responses to ACh were restored to normal with a scavenger of superoxide. Diameter of maximally dilated cerebral arterioles was less, whereas wall thickness and cross-sectional area was greater in L/ϩ mice, indicating cerebral arterioles underwent hypertrophy and remodeling. Thus, interference with PPAR␥ signaling produces endothelial dysfunction via a mechanism involving oxidative stress and causes vascular hypertrophy and inward remodeling. These findings indicate that PPAR␥ has vascular effects which are particularly profound in the cerebral circulation and provide genetic evidence that PPAR␥ plays a critical role in protecting blood vessels. (Hypertension. 2008;51:867-871.)Key Words: endothelial function Ⅲ dominant negative Ⅲ hypertension Ⅲ remodeling Ⅲ hypertrophy T he peroxisome proliferator-activated receptor gamma (PPAR␥) is a ligand-activated transcription factor which has gained prominence because of its involvement in complex diseases such as diabetes, obesity, atherosclerosis, and hypertension. Recent interest in the role of PPAR␥ in the vasculature has substantially increased because of the antiinflammatory and antioxidant effects reported for PPAR␥ agonists (reviewed by Schiffrin et al 1 ). Naturally occurring mutations in humans, resulting in either constitutive activation or impairment of PPAR␥ function, strongly support its physiological importance and illustrate the severe consequences for cardiovascular related events when PPAR␥ signaling is altered. 2 Individuals with dominant negative mutations in PPAR␥ present with early onset hypertension and elements of the metabolic syndrome. 2 Although the importance of PPAR␥ in adipose tissue is now well documented, its role in the cardiovascular system has only begun to emerge. PPAR␥ is the molecular target of the thiazolidinediones (TZDs) class of antidiabetes drugs. These drugs increase insulin sensitivity but also lower blood pressure in patients with type 2 diabetes 3 and in animal models of hypertension. 4 TZDs also improve endothelial function and reduce blood pressure in nondiabetic models of hypertension, underscoring the potential protective effects of PPAR␥ in the vessel wall. 5 PPAR␥ is expressed in endothelium and vascular muscle and there is growing evidence that PPAR␥ may have direct effects in the vasculature. 6 ...

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 (29Ϯ1 m; meanϮSE) was measured in vivo using a cranial window in anesthetized db/db and control mice. Results-Dilatation of cerebral arterioles in response to acetylcholine (ACh; 1 and 10 mol/L), but not to nitroprusside, was markedly reduced in db/db mice (eg, 10 mol/L ACh produced 29Ϯ1% and 9Ϯ1% in control and db/db mice, respectively). Superoxide levels were increased (PϽ0.05) in cerebral arterioles from db/db mice (nϭ6) compared with controls (nϭ6). Vasodilatation to ACh in db/db mice was restored to normal by polyethylene glycol-superoxide dismutase (100 U/mL). Y-27632 (1 to 100 mol/L; a Rho-kinase inhibitor) produced modest vasodilatation in control mice but much greater responses in db/db mice. N G -nitro-L-arginine (100 mol/L; an inhibitor of NO synthase) significantly enhanced Y-27632-induced dilatation in control mice to similar levels as observed in db/db mice. Conclusions-These

Abstract-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 crosssectional 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. . During maximal dilatation, the stress-strain curves in cerebral arterioles of transgenically hypertensive mice and spontaneously hypertensive mice were shifted to the right of the curves in corresponding controls, an indication that arteriolar distensibility was increased in the transgenically and spontaneously hypertensive groups. Thus, cerebral arterioles undergo remodeling and hypertrophy in transgenically hypertensive mice, but only hypertrophy in spontaneously hypertensive mice. These findings support the hypothesis that the renin-angiotensin system is an important determinant of vascular remodeling during chronic hypertension. Key Words: renin-angiotensin system Ⅲ mice Ⅲ vasculature Ⅲ remodeling Ⅲ hypertrophy Ⅲ hypertension, chronic C hronic hypertension alters the structure and mechanics of cerebral arterioles. Cerebral arterioles in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SHRSP) undergo both hypertrophy of the vessel wall and reduction in external diameter (remodeling). 1,2 Despite hypertrophy, cerebral arterioles undergo a paradoxical increase in passive distensibility of the vessel wall during chronic hypertension in SHRSP. 3 Because these alterations may contribute to the increased risk of stroke that accompanies chronic hypertension, it is important to examine determinants of these alterations in the cerebral circulation, as opposed to other vascular beds, so that we may better understand the link between chronic hypertension and stroke.Alterations in vascular structure during chronic hypertension may result from a number of determinants, including arterial pressure, 4 neurohumoral factors, 5,6 and endotheliumderived factors. 7-9 A determinant of particular interest with respect to vascular remodeling has been the renin-angiotensin system. This interest was stimulated by previous studies in which we found that angiotensin-converting enzyme (ACE) inhibitors, but not hydralazine or propranolol, attenuate remodeling of cerebral arterioles in SHRSP. 10,11 Because the ACE inhibitors lowered arterial pressure in SHRSP more effectively than hydralazine and propranolol, however, we were unable to draw definitive conclusions from these studies with regard to the direct effects of the ACE inhibitor on cerebral vascular remodeling and hypertrophy, as opposed to the effects of arterial pressure per se.A major goal of this study was to examine further the hypothesis that the renin-angiotensin system plays an important role in vascular remodeling during chronic hypertension. T...

SUMMARY Several new concepts have emerged recently regarding the effects of chronic hypertension on cerebral blood vessels. First, hypertrophy of large cerebral arteries in chronic hypertension attenuates increases in pressure of downstream vessels and protects the cerebral microvasculature. Second, In contrast to large cerebral arteries, which become less distensible during chronic hypertension, distensibility of cerebral arterioles increases during chronic hypertension despite hypertrophy of the arteriolar wall. Third, dilatation of cerebral blood vessels with disruption of the blood-brain barrier, and not vasospasm, appears to be the critical factor in the pathogenesis of hypertensive encephalopatby. This concept is supported by the finding that cerebral edema hi stroke-prone spontaneously hypertensive rats is preceded by vasodilatation and disruption of the barrier. Fourth, alterations of endotbeuum-mediated dilatation may impair vasodilator responses in chronic hypertension and predispose to ischemia. Finally, chronic hypertension impairs dilatation of collateral blood vessels hi the cerebral circulation. The implication of this finding is that increased susceptibility to cerebral infarction in chronic hypertension may be related in part to compromised responses of the collateral circulation. (Hypertension 12: 89-95, 1988) KEY WORDS • vascular mechanics • blood-brain barrier • collateral circulationT EN years ago, two concepts dominated thinking regarding the effects of chronic hypertension on the cerebral circulation. First, hypertrophy of cerebral blood vessels during prolonged hypertension was thought to lead to encroachment of the wall on the vascular lumen and to reduced vascular distensibility, thereby limiting dilator responses of cerebral vessels 1 and possibly contributing to an increase in susceptibility to cerebral infarction.2 Second, hypertensive encephalopathy was believed to result from vasospasm of cerebral vessels in response to elevation of arterial pressure, with cerebral ischemia secondary to the vasospasm. During the past 10 years, our understanding of the cerebral circulation in chronic hypertension has undergone substantial change. It is now known, for