Mechanism of Resistance Artery Contraction

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Pressure-induced (myogenic) tone is a physiological response centrally involved in autoregulation of blood flow in the brain. A fundamental mechanism involved in the regulation of cerebral artery constriction is depolarization of the smooth muscle cell membrane and increased Ca2+ entry. We have recently identified a cerebrovascular cation channel that could play a major role in both the depolarization and Ca2+-entry processes. Additional preliminary data indicate that this cation channel may be a member of the mammalian transient receptor potential (Trp) family. In the proposed studies, we will characterized the properties of these channels and determine their functional roles in the cerebral circulation. Specific Aim 1. To elucidate the biophysical and pharmacological properties of cation channels activated by cell swelling or increased pressure in cerebrovascular smooth muscle cells and the signal transduction pathways involved in their regulation. These experiments will provide evidence that will establish the role of these channels in pressure-induced depolarization of cerebral artery myocytes. Specific Aim 2. To establish the presence and functional roles of Trp channels in cerebral artery smooth muscle cells. This aim will determine which of the Trp channels are present in cerebrovascular muscle cells and what physiological roles they serve in cerebral resistance arteries. These studies will be performed using a unique combination of approaches from molecular to whole tissue levels to provide an integrated picture of cerebral artery contractile mechanisms involving membrane potential and regulation of [Ca2+]i. State-of-the-art techniques will be employed including membranes potential, cell Ca2+, and diameter measurements in intact arteries, ion channel and cell Ca2+, measurements in freshly isolated vascular smooth muscle cells, and anti- sense oligodeoxynucleotide strategies to suppress Trp channel function. The proposed studies should significantly advance our understanding of the role of cationic channels in the regulation of vascular tone in the brain and indicate novel targets for agents that could be used to correct pathological alterations in cerebral blood flow.