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。以家庭为基础的研究表明，高血压可以遗传，但很少有致病基因已被确定。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，两个重要的机制控制血管平滑肌细胞松弛已被确定。首先，已经发现了分别增加和减少肌球蛋白磷酸酶活性的蛋白激酶，从而导致细胞松弛或收缩;其次，调节平滑肌细胞静息电位的钾通道也调节血管紧张度和血压。在整个动物和人类身上的实验清楚地表明，这两个 调节平滑肌细胞松弛的基本系统对慢性血压控制具有显著作用。本申请中提供的新基因组数据以及项目2 - 4中提供的分子、细胞和动物研究表明，肌球蛋白磷酸酶或肌球蛋白轻链磷酸化状态或BK（Ca）通道的异常可导致血管功能障碍和高血压。因此，我们推测，其蛋白质产物调节平滑肌细胞收缩和舒张的关键基因的遗传变异与血管运动异常，内膜中层厚度增加和高血压有关。为了验证这一假设，我们最近交叉引用了所有与已发表的高血压相关的全基因组连锁研究有关的基因位点， 介导血管舒张的最终共同途径中的关键蛋白质。我们发现我们的三个候选基因位于与原发性高血压相关的区域，为我们的假设提供了进一步的强大动力。我们现在提议：1）确定对血管平滑肌细胞松弛重要的基因中的人类变异，这些基因存在于超过5%的美国人中，2）确定这些遗传变异是否与硝酸甘油介导的血管扩张或颈总动脉厚度增加或减少有关，以及3）确定这些基因变异与血压的关联。我们将在代表美国人横截面的三个不同群体中测试我们的假设。考虑到血管疾病的高患病率，这些研究可能提供所需的 深入了解心血管疾病的遗传原因。

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.