DESCRIPTION Hypertensive intracerebral hemorrhage (ICH) is a devastating cause of stroke associated with high morbidity and mortality, especially in African-Americans with poorly controlled hypertension. Hypertensive ICH is usually due to rupture of penetrating arterioles, such as the lenticulostriates, that have undergone pathological changes including arteriolosclerosis and formation of Charcot-Bouchard miliary aneurysms, both of which are characterized by loss of smooth muscle cells. Molecular mechanisms causing loss of smooth muscle cells in penetrating arterioles in hypertension are poorly understood, but loss of these cells leads to impaired mechanical integrity of the vessel wall that results eventually in hemorrhage. The postulates underlying this proposal are that: 1) hypertension gives rise to cellular changes that predispose to Ca-mediated apoptotic death of smooth muscle cells in penetrating arterioles; 2) the hypertension-induced predisposition to apoptosis is held in check by endothelial nitric oxide (NO), and may be unleashed by endothelial injury. The PI will use patch clamp, immunocytochemistry, digital imaging fluorescence microscopy and confocal microscopy applied to isolated cells and tissues from rats to pursue three objectives: 1) to investigate ion channel mechanisms in smooth muscle cells related to Ca channels, gap junction channels and complement channels, that may predispose or contribute to elevated [Ca]i and Ca-induced apoptosis in smooth muscle cells from penetrating arterioles in hypertension; 2) assess for long-term manifestations of hypertension coupled with endothelial injury on arteriolar smooth muscle cells, including smooth muscle cell loss, apoptosis, elevated [Ca]i and altered Bcl-2, Bax, and iNOS expression; and (3) examine the role of the endothelium-derived modulator, NO, that would act as a "physiological brake" on Ca and gap junction channels in smooth muscle, whose loss with endothelial injury would unleash unrestrained Ca influx into smooth muscle cells.