The overall hypothesis is that angiotensin II (AII) influences hypertensive vascular function and structure, in part by inducing oxidative stress characterized by increased production of superoxide anion. Superoxide anion can directly, or indirectly via inactivation of nitric oxide (NO), alter vascular reactivity and cause arterial wall remodelling, characterized by altered growth and proliferation, increased extracellular matrix production, and inflammatory cell infiltration. These alterations involve paracrine regulation between intimal, medial, and adventitial cells. Preliminary Studies indicate that the adventitia can produce superoxide anion which can regulate the activity of endothelial NO, and that cytokines induce nitric oxide synthase primarily in adventitia. AII causes rapid changes in growth and structural characteristics of aortic cells, and these effects are not due exclusively to the increased blood pressure. AII also rapidly increases the production of superoxide anion in vascular wall cells. The objective is to determine the extent to which the changes in the vascular wall caused by AII are mediated by an increase in superoxide anion production.
The Specific Aims are: 1) To determine if early stages of AII-induced hypertension are accompanied by increases in superoxide anion production or changes in its rate of degradation, as well as the role that this oxidative stress has in altered growth, extracellular matrix formation, and inflammatory cell infiltration, 2) To determine the role that modulation of NO by superoxide anion plays in the phenotypic changes caused by AII-induced hypertension, and 3) To determine the importance of hypertension per se, and mechanisms responsible for AII-induced oxidative stress, as well as the role of oxidative stress in aortic phenotypic changes in an AII-dependent model of hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL055620-02
Application #
2519544
Study Section
Cardiovascular and Renal Study Section (CVB)
Project Start
1997-09-01
Project End
2000-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
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