Regulation of vascular form and function is a dynamic process that depends on the complex integration of responses and activities by vascular cells to a variety of stimuli. In response to these stimuli, the vascular system can mediate numerous physiological processes, rapidly alter vessel diameter to control blood flow, and grow new vessel elements (angiogenesis). Although seemingly separate activities, all of these operations constitute the means by which the vascular system maintains tissue homeostasis and thus represent a single, albeit highly integrative, function. My research career goal is to establish an interdisciplinary vascular research program aimed at understanding the molecular determinants of vascular form and function related to supporting tissue homeostasis. The research development plan to attain this goal is centered around the integration of focused research projects examining specificity in endothelial cell signal transduction, the establishment of vascular tone during vessel remodeling, and the genetic control of vascular growth. The objectives of this plan are to create a highly interactive research team, expand collaborations with accomplished imaging scientists, and gain further expertise in molecular genetics. In large vessel endothelial cells, intracellular calcium pools are managed by two sarco(endothelial cell)plasmic calcium ATPases (SERCA); the uniquely expressed SERCA3 and the ubiquitous SERCA2b pumps. The goal of the research that will examine endothelial cell signal transduction and provide the basis for expanding my collaborative efforts is to test the hypothesis that endothelial cells utilize distinct intracellular calcium pools, as defined by these two SERCA pumps, to mediate responses to different types of stimuli by demonstrating, through completion of four specific aims, that the calcium pool maintained by SERCA3 participates in a subset of endothelial cell and vascular physiological responses.
Specific Aims I and 2 will characterize the functional specificity of the SERCA3- and SERCA2b-managed calcium pools within the endothelial cell.
Specific Aims 3 and 4 will extend this analysis into the intact animal by examining the role of SERCA3 in vascular function. Mice deficient in the SERCA3 pump and endothelial cells from these mice will provide the experimental basis for these studies. Selective differences observed between cells and vessels of the two mice can be attributed to the absence of calcium stores established by SERCA3 and indicate those processes relying on this calcium pool. Completion of these aims will provide further insight into how specificity, and thus regulation, in signal transduction in endothelial cells is ,established.
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