The Program Project Grant integrates molecular and physiological approaches to examine regulation of cerebral blood vessels under physiological and pathophysiological conditions. The program represents an interactive and productive group of investigators with complimentary areas of expertise who are committed to studies of cerebral circulation. The Program has several themes: First, molecular and functional studies are proposed to examine the role of endothelium and nitric oxide in regulation of cerebral vascular function and structure. Second, state-of-the-art molecular approaches are used throughout the program, with strong emphasis on gene transfer and genetically-engineered mice. Third, a major goal is to understand cerebral vascular pathophysiology and risk factors for stroke. Studies are proposed to examine mechanisms by which chronic hypertension, byperhomo-cysteinemia, and inflammatory stimuli alter cerebral vessels. The Program has several strengths; First, the investigators have a long history of interactive studies of cerebral vessels under physiological and pathophysiological conditions. Second, strong new investigators with key expertise have been integrated into the program. Preliminary data indicate feasibility of new approaches which are proposed. Third, the investigators are leaders in physiological studies of cerebral vascular endothelium, nitric oxide, and potassium channels. They also are leaders in studies of cerebral vascular dysfunction and structural changes during pathophysiological conditions, including chronic hypertension and hyper-homocysteinemia. Fourth, the investigators use diverse, sophisticated physiological approaches in their studies. Molecular approaches now have been incorporated to facilitate novel insight into cerebral vascular structure and function. The program consists of four projects supported by three core facilities: Administration, Transgenic Animal Core, and a Vector Core. This integrated, multidiscriplinary approach is intended to facilitate rapid progress, and more penetrating insight, in understanding mechanisms that affect cerebral blood vessels.