The study of adaptation mechanisms in structure and function of blood vessels in response to physical stress is important in human health and disease. The general objective of this proposal is to elucidate how a chronic increase in stretch mediated by increase in blood pressure or blood flow influences arterial function through alterations in mechanical and structural properties and molecular remodeling. This proposal will clarify the physical stimuli and the associated responses that signify hypertension as important risk factors for CAD. The central hypothesis is that the circumferential stretch induced by increase in pressure (hypertension) or dilatation (FO) affects the AT1R which in turn upregulates Nicotinamide Adenine Dinucleotide Phosphate (NADPH) oxidase system. The latter is a major source of O2- and causes an imbalance in oxidative stress which leads to coronary vascular (endothelial and smooth muscle) dysfunction. To achieve this objective, we set the following four Specific Aims: 1) To identify the role of circumferential stretch as the stimulus for AT1R-mediated O2- production in ex-vivo vessels during acute hypertension and FO, 2) To establish upregulation of AT1R and its role on the balance between NO and O2- chronically during the progression of hypertension and/or FO due to the stretch stimulus identified in Aim 1, 3) To elucidate the role of NADPH oxidase as well as other regulatory enzymes for NO (endothelial NO synthase, eNOS) and O2- dismutase (SOD) in limiting NO bioavailability in Aim 2, and 4) To quantify the endothelial and smooth muscle cell dysfunction of coronary arteries due to the oxidative imbalance in Aims 1-3. This research will clarify the role played by increased blood pressure or flow on coronary blood vessel remodeling;state the results mathematically in order to clarify the stimulus for molecular, structural, mechanical and functional remodeling that signifies hypertension and FO as important risk factors for CAD. It is expected that these studies will define the mechanisms responsible for reduced NO bioavailability and endothelial dysfunction and lead to target therapeutic drug developments for coronary heart disease. The long-term goal of this research is to develop optimal therapies to restore the oxidative balance in CAD. The approaches may include targeting the AT1R, NADPH oxidase system and/or restoration of eNOS functionality.
Coronary heart disease remains the major cause of morbidity and mortality in the U.S. and is very much on the rise around the world. There is no doubt that hemodynamic forces (blood pressure and blood flow) affect the angiotensin receptors and oxidative balance which lead to coronary artery disease (CAD). The long-term goal of this research is to develop optimal therapies to restore the oxidative balance in CAD.
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