GENETICS OF VASOREGULATION AND CARDIOVASCULAR RESPONSES

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Essential hypertension and vascular disease affects over 50 million Americans. Family-based studies show that hypertension can be inherited, however few causative genes have been identified. In search of causes of hypertension we have studied mechanisms regulating blood vessel contraction and relaxation, which contribute to blood pressure regulation. From this work two important mechanisms controlling vascular smooth muscle cell relaxation have been identified. First, protein kinases that increase and decrease myosin phosphatase activity causing cellular relaxation or contraction, respectively, have been found. Second, a potassium channel that regulates the resting potential of the smooth muscle cell, also regulates vasomotor tone and blood pressure. Experiments in whole animals and humans demonstrate clearly that these two fundamental systems regulating smooth muscle cell relaxation have a marked effect on chronic blood pressure control. New genomic data presented in this application and molecular, cellular and animal studies presented in Projects 2-4 show that abnormalities of either the myosin phosphatase or myosin light chain phosphorylation state or the BK(Ca) channel can cause vascular dysfunction and hypertension. We therefore hypothesize that genetic variations in the critical genes whose protein products regulate smooth muscle cell contraction and relaxation are associated with abnormal vasomotion, increased intima-media thickness and hypertension. To test this hypothesis we recently cross-referenced all loci implicated by published hypertension-associated genome-wide linkage studies with the location of genes that encode critical proteins in the final common pathway mediating vasorelaxation. We discovered that three of our candidate genes are located in regions associated with essential hypertension, providing a further strong impetus to the testing of our hypothesis. We now propose: 1) to identify human variants in genes important for vascular smooth muscle cell relaxation that are present in more than five percent of Americans, 2) determine if these genetic variants are associated with increased or reduced nitroglycerin-mediated blood vessel dilation or common carotid artery thickness, and 3) identify the association of these gene variants with blood pressure. We will test our hypotheses in three different groups representative of a cross-section of Americans. Considering the high prevalence of blood vessel disorders these studies may provide needed insight into the genetic causes of cardiovascular disease.