The major focus of this project is to utilize in vivo models, including genetically altered animals, to determine the role of the renin- angiotensin system and nitric oxide in provoking cardiac and vascular changes that occur in response to experimental hypertension. The first specific aim is to study the effects of hypertension on the pathogenesis of atherosclerosis in transgenic mice models that develop atherosclerosis spontaneously. These studies will assess cellular and extracellular responses in the aorta of apoE deficient mice that will be bred to combine genetic traits that predispose to hyperlipidemia and hypertension. The availability of "knockout" mice for apoE, which develop atherosclerotic lesions in a predictable temporal pattern, will facilitate development of animals that combine these hyperlipidemic traits with the alteration of genes thought to modulate blood pressure. The development of these hybrid mice will be performed in collaboration with Dr. Paigen using approaches outlined in her proposal. Pharmacological experiments will be performed in hyperlipidemic mice to determine the role of the nitric oxide generating systems and the renin-angiotensin system in the pathogenesis of atherosclerotic lesions. Experiments designed to determine mechanisms for the attenuation of atherosclerosis by anti-hypertensive drugs will be initiated. The second specific aim is to study the interrelationships between the renin-angiotensin system and nitric oxide (NO) on the development of cardiac injury during experimental hypertension. Both rats and mice which have been shown by us to develop rapid and extensive responses in both heart and aorta in response to angiotensin ll (ang II) infusion will be used as experimental models. The cardiac responses will be examined by biochemical and histological techniques, including the use of cell-specific markers for identification of cell types and stage of cell cycle, and biochemical methods that quantitatate selective changes in gene expression and cbemical composition of both arterial and cardiac lesions. The potential mechanisms involved in these responses will be dissected out by different approaches, including: a) selective use of vasoactive agonists and antagonists to separate the effects of ang II, NO and blood pressure on the process; b) the use of transgenic mice lacking selective receptors for either angiotensin or alpha-adrenergic receptors and mice with selective impairment in the immune system. An hypothesis to be tested is that cell growth and/or proliferation are regulated in part by opposing effects of ang II and NO. The potential participation of cytokines produces by macrophages and/or lymphocytes to the remodelling processes will be assessed.