GENETICS OF VASOREGULATION AND CARDIOVASCULAR RESPONSES

原发性高血压和血管疾病影响着超过5000万美国人。基于家庭的研究表明，高血压可以遗传，但很少有致病基因被确定。为了寻找高血压的原因，我们研究了调节血管收缩和舒张的机制，这有助于血压调节。从这项工作中，已经确定了控制血管平滑肌细胞松弛的两个重要机制。首先，已经发现分别引起细胞松弛或收缩的肌球蛋白磷酸酶活性增加和减少的蛋白激酶。其次，钾通道调节平滑肌细胞的静息电位，也调节血管舒缩张力和血压。在整个动物和人类身上进行的实验清楚地证明了这两点

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.