Hypertension is a complex pathophysiological state that is the primary predisposing factor for many cardiovascular diseases. Overwhelming evidence has established that altered renin-angiotensin system (RAS) function plays a key role in the development and establishment of hypertension. While traditional pharmacological agents that inhibit the RAS are effective antihypertensive therapies, hypertension remains the number one health problem for our country. We believe that new and innovative approaches must be initiated to achieve successful control and cure of this disease. We tested the hypothesis that genetic targeting of the RAS would result in long-term control of hypertension. Our studies have been very successful and have demonstrated that antisense (AS) inhibition of the RAS causes long-term attenuation of hypertension. Thus, we have established the "proof of concept" that gene transfer strategy is technically feasible and intellectually sound for treatment of this disease. Despite our success in animal studies the AS technology presents limitations for its use in humans. In addition, critical experimental, mechanistic and gene delivery issues are yet to be addressed. Therefore, our objective during this grant period is to resolve these issues by using angiotensin converting enzyme 2 (ACE2) as the target gene. We propose to test the hypothesis that "overexpression of endothelial ACE2 will result in long-term antihypertensive effects that include both decreases in high BP and reversal of cardiovascular pathophysiologies". This hypothesis will be tested by the following three specific aims: (i) investigate whether ACE2 gene delivery by a lentiviral vector prevents the development of hypertension; (ii) determine if ACE2 overexpression reverses established hypertension, and (iii) investigate the role of vascular endothelial ACE2 in the reversal of hypertension. State-of-the-art techniques of systemic gene transfer, knockin transgenics and molecular biology will be used to accomplish these aims. We believe that such a physiological genomic approach is ideal and will have high impact in the control of this complex disease. Thus, the outcome of our research has the potential to be readily adapted for the treatment and possible cure of human hypertension and other cardiovascular diseases.