COBRE: UVM MED PROJ 5: CEREBRAL VASOSPASM MECHANISM IN SUBARACHNOID HEMORRHAGE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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. Peviously we have reported enhanced pressure-induced constriction in small diameter cerebral arteries obtained from a rabbit model of subarachnoid hemorrhage. Our current work indicates that fundamental changes in Ca2+ signaling and voltage-dependent Ca2+ channel (VDCC) properties leads to this enhanced constriction of cerebral arteries. Our recently published study (Ishiguro et al., Circ. Res., 2005) demonstrates, for the first time, the expression of a novel "R-type" calcium channel (encoded by the gene CaV 2.3) in cerebral arteries during vasospasm. We propose that R-type calcium channels contribute to enhanced cerebral artery constriction following aneurysm rupture and may represent a novel therapeutic target in the treatment of neurological deficits associated with vasospasm. Our preliminary data also suggests oxyhemoglobin, a blood component linked to vasospasm, decreases voltage-dependent potassium (KV) channel activity to indirectly increase VDCC activity via membrane potential depolarization. In the upcoming year we will focus our efforts on exploring mechanisms involved in changes in Ca2+ channel expression associated with subarachnoid hemorrhage. Also we will continue our collaboration with Dr. Moreilli examining oxyhemogobin-induced potassium channel suppression. This work should significantly enhance current knowledge with respect to Ca2+ signaling and constriction of cerebral arteries in health and disease.