The major objective of this proposal is to elucidate the functional significance of several novel mediators and mechanisms involved in regulating intracellular Ca2+ and contractility of cerebral arteries. Through their constrictor and dilator activity, cerebral arteries tightly regulate blood flow and capillary perfusion pressure within a range that sustains normal brain function. We have discovered that members of the transient receptor potential (TRP) superfamily of ion channels are present in cerebral arteries and that these channels play novel, specific and diverse roles in cerebrovascular function: TRPM4 subserves mechanotransduction..
(Aim 1); TRPC3 transduces vasoconstrictor receptor responses (Aim 2);TRPV4 has a unique role in endothelial/smooth muscle communication (Aim 3). We propose to elucidate the properties of these different TRP channels in the cerebral vasculature, and determine their vasoregulatory roles.
Specific Aim 1 : To define the properties, signal coupling mechanisms, and unique functional roles of TRPM4 channels in cerebral arteries. These experiments will reveal the biophysical properties of TRPM4 channels in native vascular smooth muscle, determine their possible mechanosensitive nature, and consider their in vivo functionality.
Specific Aim 2 : To elucidate the roles and regulation of nativeTRPCSchannels in agonist induced Ca2+ influx and cerebral vasoconstriction. These experiments will demonstrate the possible role of TRPC3 channels as receptor-operated cation channels in vascular smooth muscle and elucidate the mechanisms by which vascular TRPC3 activity is controlled.
Specific Aim 3 : To define and differentiate the roles of TRPV4 channels in cerebral arteries. Our preliminary data suggest a novel and unexpected role for TRPV4 channels in endothelium-dependent vasodilator activity, involving endothelium-derived hyyperpolarizing factors, TRPV4 channels, and local Ca2+ release events (Ca2+ sparks).
In Aim 3 we will reveal the specific mechanisms involved in these responses. The use of multiple, state-of-the-art techniques (membrane potential, cell Ca2+, diameter, ion channel recording, in vivo blood flow measurements, gene silencing) and a unique combination of approaches from the molecular to the whole animal will provide a comprehensive view of the role of TRP channels in the cerebral circulation and indicate novel targets for agents that could be used to correct pathological alterations in cerebral blood flow.
|Dabertrand, Fabrice; Nelson, Mark T; Brayden, Joseph E (2013) Ryanodine receptors, calcium signaling, and regulation of vascular tone in the cerebral parenchymal microcirculation. Microcirculation 20:307-16|
|Dabertrand, Fabrice; Hannah, Rachael M; Pearson, Jessica M et al. (2013) Prostaglandin E2, a postulated astrocyte-derived neurovascular coupling agent, constricts rather than dilates parenchymal arterioles. J Cereb Blood Flow Metab 33:479-82|
|Dabertrand, Fabrice; Nelson, Mark T; Brayden, Joseph E (2012) Acidosis dilates brain parenchymal arterioles by conversion of calcium waves to sparks to activate BK channels. Circ Res 110:285-94|
|Baylie, R L; Brayden, J E (2011) TRPV channels and vascular function. Acta Physiol (Oxf) 203:99-116|
|Nystoriak, Matthew A; O'Connor, Kevin P; Sonkusare, Swapnil K et al. (2011) Fundamental increase in pressure-dependent constriction of brain parenchymal arterioles from subarachnoid hemorrhage model rats due to membrane depolarization. Am J Physiol Heart Circ Physiol 300:H803-12|
|Earley, Scott; Brayden, Joseph E (2010) Transient receptor potential channels and vascular function. Clin Sci (Lond) 119:19-36|
|Earley, Scott; Pauyo, Thierry; Drapp, Rebecca et al. (2009) TRPV4-dependent dilation of peripheral resistance arteries influences arterial pressure. Am J Physiol Heart Circ Physiol 297:H1096-102|
|Brayden, Joseph E; Earley, Scott; Nelson, Mark T et al. (2008) Transient receptor potential (TRP) channels, vascular tone and autoregulation of cerebral blood flow. Clin Exp Pharmacol Physiol 35:1116-20|
|Earley, Scott; Straub, Stephen V; Brayden, Joseph E (2007) Protein kinase C regulates vascular myogenic tone through activation of TRPM4. Am J Physiol Heart Circ Physiol 292:H2613-22|
|Reading, Stacey A; Brayden, Joseph E (2007) Central role of TRPM4 channels in cerebral blood flow regulation. Stroke 38:2322-8|
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