Vasospasm occurs unexpectedly and unpredictably during peripheral and aortocoronary bypass graft reconstructions. We propose that some forms of vasospasm are due to impaired cyclic nucleotide-dependent vasorelaxation of the vascular smooth muscle. Using a model of vasospasm, human umbilical artery smooth muscle (HUASM), we have determined that a major phosphoprotein substrate during cyclic nucleotide-dependent vasorelaxation is a small heat shock protein, HSP2O. Other investigators have implicated, another small HSP, HSP27, in contraction of smooth muscles and have found that HSP27 expression is increased, specifically in the vasculature, by stress. The hypothesis of this investigation is that the phosphorylation of HSP2O modulates cyclic nucleotide-dependent vasorelaxation and that alterations in the expression or phosphorylation of HSP27 lead to the inhibition of HSP2O phosphorylation and vasospasm.
The specific aims are to: 1) Determine the signal transduction events that lead to the phosphorylation of small HSPs during contraction and relaxation of vascular smooth muscles; and 2) Determine the specific functions of small HSPs in vascular smooth muscle contraction and relaxation. Physiologic responses will be determined in a muscle bath and correlated with signal transduction events. Responses in normal vascular smooth muscle (bovine carotid artery smooth muscle) will be compared to the muscle that is a model of vasospasm (human and bovine umbilical artery smooth muscle). Using these systems we plan to determine the specific role of heat shock proteins in vasospasm.
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