Cerebral artery Ca2+ signaling & subarachnoid hemorrhage

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DESCRIPTION (provided by applicant): Cerebral vasospasm following aneurysm rupture and subarachnoid hemorrhage (SAH) is a devastating disorder that inflicts disability and death upon thousands of individuals each year. Currently, little is known regarding the cellular mechanisms of this blood-induced cerebral artery narrowing. This proposal builds upon our work indicating that fundamental changes in Ca2+ signaling and voltage-dependent Ca2+ channel (VDCC) properties lead to enhanced constriction of cerebral arteries in an established rabbit SAH model. We have obtained exciting preliminary data indicating that SAH leads to enhanced Ca2+ entry in cerebral artery myocytes through: 1) Enhanced VDCC currents due to the emergence of R-type VDCCs (Cav 2.3), which are resistant to conventional ("L-type") calcium channel antagonists; and 2) Oxyhemoglobin, a blood component linked to vasospasm, which decreases sarcoplasmic reticulum Ca2+ release events (Ca2+ sparks) to indirectly increase VDCC activity via membrane potential depolarization. The proposed work will take an integrative approach to elucidate the impact of SAH on small diameter cerebral arteries critical to cerebral blood flow regulation by employing innovative and sophisticated electrophysiological, cell imaging and molecular biology techniques. Specific Aim 1 will test the central hypothesis that cerebral artery myocytes from control animals contain a single type of VDCCs (L-type), while cerebral artery myocytes from SAH animals contain two types of VDCCs (L-type and R-type). We propose R-type VDCCs as novel targets to treat SAIl, and that their expression indicates increased likelihood of cerebral vasospasm. Specific Aim 2 will determine the role Ca2+ sparks play in diameter regulation of cerebral arteries following SAH. We will examine whether the communication between sarcoplasmic reticulum ryanodine receptors (RyRs) and VDCCs is disrupted following SAH. The emergence of R-type VDCCs in cerebral artery myocytes following SAH provides the unique opportunity to compare the coupling strength of L-type and R-type VDCCs to RyRs in native smooth muscle. Specific Aim 3 will define the cellular events linking oxyhemoglobin to both enhanced VDCC expression and inhibition of Ca2+sparks. This study should significantly enhance current knowledge with respect to Ca2+signaling and constriction of cerebral arteries in health and disease and provide insight into possible new therapies for the treatment of cerebral vasospasm.