MICROVASCULAR ADAPTATIONS IN HYPERTENSION

当高血压患者的大动脉和其他大动脉肥厚时， 外周血管阻力因小动脉和血管重构而增加 小动脉进入具有较小管腔的血管，与变化无关 在墙体横截面积内。这项研究提案的目标是 检验小动脉重塑由一种 血管平滑肌细胞和壁基质成分对慢性阻塞性肺疾病的调节 血管收缩采用三步法。第一，扫描和 将使用透射电子显微镜来确定静息长度 血管内皮细胞所占的壁面积百分比， 一肾一夹中的胶原蛋白、基底膜和平滑肌 (1KlC)高血压大鼠。第二，假设慢性 血管收缩在重塑之前将通过测量小动脉来测试 1KlC大鼠脊髓斜方肌的肌张力及其假说 压力升高是重塑的必要刺激将在 主动脉缩窄的实验研究。第三，分子基础 将使用原位杂交技术研究肥大和重塑 生长因子和基质蛋白在主动脉和小动脉中的表达。这 技术将首先应用于14天输液模型 血管紧张素II的降压剂量，因为它可能在肾脏中起作用 高血压及其对特定生长因子的影响 在培养的细胞上进行实验。将对主动脉和小动脉进行探查 碱性成纤维细胞生长因子、转化生长因子-β、PDGF-A链、α-肌动蛋白、胶原和层粘连蛋白的mRNA表达。 图像分析将用于对原位杂交信号进行量化。 假设平滑肌细胞的周转发生在 重塑将通过免疫细胞化学检测增殖细胞 核抗原(细胞周期蛋白)。然后，这些技术将被应用于船舶 来自1KlC高血压大鼠。结果将允许结构之间的联系 特定基因表达的改变局限于细胞类型，即， 血管内皮细胞或平滑肌细胞。两项研究结果的比较 大动脉和小动脉可能表明为什么以前的肥厚而 后一种改建。因此，这些研究将进一步描绘出 从体外实验中建议的个体生长因子并揭示 构成基础的细胞类型之间的旁分泌关系 高血压小动脉重构和血管阻力增加。

While the aorta and other large arteries hypertrophy in hypertension, peripheral vascular resistance is increased by remodeling of arterioles and small arteries into vessels with smaller lumens, independently of changes in wall cross-sectional area. The goal of this research proposal is to test the overall hypothesis that arteriolar remodeling consists of an adjustment of smooth muscle cells and wall matrix components to chronic vasoconstriction using a three stage approach. First, scanning and transmission electron microscopy will be used to determine resting length of smooth muscle cells and percent of wall occupied by endothelium, collagen, basement membrane, and smooth muscle in one-kidney, one-clip (lKlC) hypertensive rats. Second, the hypothesis that chronic vasoconstriction precedes remodeling will be tested by measuring arteriolar tone in the spinotrapezius muscle of lKlC rats and the hypothesis that elevated pressure is a necessary stimulus for remodeling will be tested in experiments on aortic coarctation. Third, the molecular basis of hypertrophy and remodeling will be studied using in situ hybridization for mRNA of growth factors and matrix proteins in aortas and arterioles. This technique will be applied first to the model of 14-day infusion of subpressor doses of angiotensin II because of its possible role in renal hypertension and its effect on specific growth factors as suggested by experiments on cultured cells. Aortas and arterioles will be probed for mRNA for bFGF, TGF-beta, PDGF-A-chain, alpha-actin, collagen and laminin. Image analysis will be used to quantify the in situ hybridization signal. The hypothesis that turnover of smooth muscle cells occurs during remodeling will be tested by immunocytochemistry for proliferating cell nuclear antigen (cyclin). These techniques will then be applied to vessels from lKlC hypertensive rats. Results will allow the linkage of structural changes to specific gene expression localized to a cell type, i.e., endothelial cells or smooth muscle cells. Comparisons of results in the aorta and arterioles may indicate why the former hypertrophies while the latter remodels. Thus these studies will further delineate the role of individual growth factors suggested from in vitro experiments and reveal paracrine relationships between cell types that form the basis of arteriolar remodeling and increased vascular resistance in hypertension.