Studies are proposed to examine effects of chronic hypertension and aging on cerebral blood vessels. The goals are to examine mechanisms and consequences of alterations in cerebral vascular structure and function during chronic hypertension, and to examine mechanisms that may contribute to altered structure and function of cerebral vessels during aging. Several hypotheses will be tested. First, studies are proposed to examine mechanisms by which chronic hypertension alters structure and mechanics of cerebral arterioles. Three hypotheses will be tested using an in vivo method to examine vascular distensibility, and morphometric methods to examine vascular composition. First, normotensive rats will be treated chronically with a blocker of nitric oxide production to test the hypothesis that endothelium-derived relaxing factors may contribute to hypertrophy and remodeling of cerebral arterioles during chronic hypertension. Second, normotensive Wistar Kyoto rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) will be treated chronically with a cyclooxygenase inhibitor and a thromboxane A2 receptor antagonist to examine the hypothesis that a cyclooxygenase-dependent, endothelium-derived constricting factor may contribute to hypertrophy with increases in distensibility and remodeling of cerebral arterioles in SHRSP. Finally, to test the hypothesis that heparin-like glycosaminoglycans may play a role in alterations of cerebral vascular structure and mechanics, heparin will be infused chronically in WKY and SHRSP. Second, studies are proposed to examine consequences of altered structure and mechanics to cerebral vascular function during chronic hypertension. In one study, the hypothesis that large, as well as small, cerebral vessels contribute to enhanced autoregulatory constriction in chronic hypertension will be examined by determining resistance of large and small cerebral vessels in WKY and SHRSP during acute increases in arterial pressure. In another study, a newly developed in vitro method will be used to test the hypothesis that both remodeling of cerebral arterioles and reduced distensibility of large cerebral arteries may be important mechanisms by which structural changes alter cerebral vascular responses during chronic hypertension. Third, smooth muscle in cerebral arterioles undergoes atrophy during aging with a reduction in arteriolar distensibility. Studies are planned to examine the hypotheses that alterations in structure and mechanics of cerebral arterioles during aging may be associated with, and perhaps due in part to, 1) reduction in arteriolar pulse pressure and dP/dt, 2) prolonged exposure of the vessel wall to oxygen-derived free radicals, and 3) increases in heparin-like glycosaminoglycans in extracellular matrix of the arteriolar wall. The studies have considerable potential to clarify the mechanisms through which chronic hypertension and aging modify cerebral vascular structure and function. In addition, the studies should provide additional insight into the interaction of structure and function in the vessel wall.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL022149-16
Application #
3336719
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Project Start
1978-04-01
Project End
1997-04-30
Budget Start
1993-05-01
Budget End
1994-04-30
Support Year
16
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of Iowa
Department
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Chan, Siu-Lung; Baumbach, Gary L (2013) Deficiency of Nox2 prevents angiotensin II-induced inward remodeling in cerebral arterioles. Front Physiol 4:133
Beyer, Andreas M; Baumbach, Gary L; Halabi, Carmen M et al. (2008) Interference with PPARgamma signaling causes cerebral vascular dysfunction, hypertrophy, and remodeling. Hypertension 51:867-71
Baumbach, Gary L; Didion, Sean P; Faraci, Frank M (2006) Hypertrophy of cerebral arterioles in mice deficient in expression of the gene for CuZn superoxide dismutase. Stroke 37:1850-5
Didion, Sean P; Lynch, Cynthia M; Baumbach, Gary L et al. (2005) Impaired endothelium-dependent responses and enhanced influence of Rho-kinase in cerebral arterioles in type II diabetes. Stroke 36:342-7
Baumbach, Gary L; Sigmund, Curt D; Faraci, Frank M (2004) Structure of cerebral arterioles in mice deficient in expression of the gene for endothelial nitric oxide synthase. Circ Res 95:822-9
Chillon, Jean-Marc; Baumbach, Gary L (2004) Effects of chronic nitric oxide synthase inhibition on cerebral arterioles in Wistar-Kyoto rats. J Hypertens 22:529-34
Chillon, Jean-Marc; Baumbach, Gary L (2004) Effects of indapamide, a thiazide-like diuretic, on structure of cerebral arterioles in hypertensive rats. Hypertension 43:1092-7
Baumbach, Gary L; Sigmund, Curt D; Faraci, Frank M (2003) Cerebral arteriolar structure in mice overexpressing human renin and angiotensinogen. Hypertension 41:50-5
Baumbach, Gary L; Sigmund, Curt D; Bottiglieri, Teodoro et al. (2002) Structure of cerebral arterioles in cystathionine beta-synthase-deficient mice. Circ Res 91:931-7
Chillon, J M; Baumbach, G L (2001) Effects of an angiotensin-converting enzyme inhibitor and a beta-blocker on cerebral arteriolar dilatation in hypertensive rats. Hypertension 37:1388-93

Showing the most recent 10 out of 36 publications