VASCULAR CELL PHENOTYPES IN PULMONARY HYPERTENSION

描述：(根据申请者的抽象和具体目标改编。) 肺损伤血管壁迅速增厚 高血压(PH)，尤其是管腔内的微血管 限制增加肺血管阻力和压力。AS单元格 肥大和增殖使管腔、细胞和基质变窄。 组件被组织成新的内膜、内层和外膜层， 并且新的收缩细胞在正常的非肌肉节段中发展(即， 新生肌化)。丝状蛋白的表达与 伴随这种生长模式的血管细胞分化 仍未确定其特征。结果表明，中间细胞和迁移 间质成纤维细胞首先聚集到损伤的血管壁上 然后是内膜和中层细胞层；从结构上讲，它们获得了 与收缩有关的微丝和细胞器，但仅在某些 肌球蛋白优先表达。这些细胞合成原弹性蛋白， 和弹性层(E)的形成，对其内部的组织至关重要 脉管壁。该应用程序建议存在地区性和 血管内皮细胞中平滑肌肌球蛋白的差异性调节 PH中的微血管节段。假设是在墙内 重塑，细胞的中间途径迅速增加肌球蛋白 表达，而成纤维细胞途径的表达增加 细胞骨架蛋白。具体目标是：1)确定 通过分析肌动蛋白的表达来确定细丝蛋白的分布 高分辨率的微丝、中间丝和肌丝 免疫细胞化学；2)用亚细胞定义细胞晶格 高分辨率显微镜下纤维和细胞器的分布；3) 用原位技术建立肌球蛋白和原弹性蛋白基因表达的调控 以及4)确定亲缘关系挑战的影响 低氧恢复呼吸对“高氧适应断奶肺”的影响 空气。通过定义收缩和细胞骨架的组织和类型 细丝，目标是理解发生的表型转换 在特定血管节段的细胞中，当它们重建血管时 PH值中的墙体。

DESCRIPTION: (Adapted from the applicant's abstract and Specific Aims.) The walls of injured blood vessels rapidly thicken in pulmonary hypertension (PH), especially those of the microvessels, where lumen restriction increases pulmonary vascular resistance and pressure. As cell hypertrophy and proliferation narrow the vessel lumen, cell and matrix components are organized into new intimal, medial, and adventitial layers, and new contractile cells develop in normally nonmuscular segments (i.e., neomuscularization). The expression of filament proteins responsible for the vascular cell differentiation that accompanies this pattern of growth remain uncharacterized. Results show that intermediate cells and migrating interstitial fibroblasts recruited to the injured vessel wall form first intimal and then medial cell layers; structurally, they acquire microfilaments and organelles associated with contraction, but only in some is myosin preferentially expressed. Tropoelastin synthesis by these cells, and elastic lamina(e) formation, are critical to their organization within the vessel wall. The application proposes that there is regional and differential regulation of smooth muscle myosin in the cells of the microvascular segments in PH. The hypothesis is that during wall remodeling, cells of the intermediate pathway rapidly increase myosin expression while those of the fibroblast pathway increase expressionof cytoskeletal proteins. The Specific Aims are to: 1) identify the distribution of filament proteins, by analyzing the expression of actin microfilaments, intermediate filaments, and myofilaments by high resolution immunocytochemistry; 2) define the cell lattice by the subcellular distribution of filaments and organelles by high resolution microscopy; 3) establish regulation of myosin and tropoelastin mRNA expression by in situ hybridization; and 4) establish the effects of the challenge of relative hypoxia on the "hyperoxia-adapted and weaned lung" by return to breathing air. By defining the organization and type of contractile and cytoskeletal filaments, the goal is to understand the phenotypic switching that occurs in the cells of specific vascular segments as they remodel the vascular wall in PH.