The goals of this proposal focus on the action of alpha1 adrenergic receptors particularly in vascular smooth muscle with emphasis on regulation of these receptors and their signaling mechanisms.
Specific Aim 1 : Signal transduction mechanisms of alpha receptors in vascular smooth muscle. During the past funding period the investigators have developed evidence indicating that alpha1 receptors in vascular smooth muscle activate a variety of signaling pathways including MAP kinases and proto-oncogene expression. The primary purpose of this aim is to characterize alpha1 stimulation of these and other signaling pathways in vascular smooth muscle. Since they have found that nitric oxide inhibits the activation of proto- oncogene expression in intact aortas, the second aspect of this aim is to identify signaling mechanisms by which nitric oxide modifies responses to alpha1 receptor stimulation. The third aspect of this aim is to determine alterations in these signaling pathways induced by desensitizing alpha1 responses in smooth muscle after prolonged activation of alpha1 adrenergic receptors.
Specific Aim 2 : Differential coupling of alpha1 receptors to signaling pathways. In preliminary experiments, the investigators have found that specific alpha1 receptor subtypes have different signaling mechanisms or capacities to induce gene expression in cultured cells. The purpose of this aim is to characterize further the mechanisms for these differential effects of alpha1 adrenergic receptor subtypes. They propose to apply this information to investigate the signaling mechanisms involving a constitutively active mutation of the alpha1B receptor which leads to stimulation of cell division in transfected cells even in the absence of catecholamines.
Specific Aim 3 : Metabolic effects of alpha1 receptors in vascular smooth muscle and gene regulation. They have found that insulin and IGF-1 induce expression of specific alpha1 receptor subtypes in vascular smooth muscle cells. Also, their preliminary results indicate that activation of alpha1 receptors induces expression of LDL receptors and lipid uptake in smooth muscle cells. These results may have mechanistic implications for the adverse effects of elevated insulin concentrations in hypertension and the beneficial effects of alpha adrenergic antagonists on cardiovascular risk. The purpose of this specific aim is to extend and deepen these observations of the effects of insulin and alpha1 agonists on vascular cell biology. The proposed experiments have particular relevance for the pharmacological role of alpha1 receptors in blood vessels; as well, the underlying mechanisms should have more general importance in understanding the biology of these receptors which transduce many of the actions of the sympathetic nervous system in health and disease.
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