VASCULAR CELL PHENOTYPES IN PULMONARY HYPERTENSION

描述：（改编自申请人的摘要和具体目标。） 肺损伤血管壁迅速膨胀， 高血压（PH），特别是那些微血管，其中管腔 限制增加肺血管阻力和压力。 如细胞 肥大和增生使管腔、细胞和基质变窄 组分被组织成新的内膜层、中层和外膜层， 并且新的收缩细胞在正常的非肌肉节段中发育（即， 新肌化）。 丝蛋白的表达，负责 伴随这种生长模式的血管细胞分化 仍然没有特征。 结果表明，中间细胞和迁移 间质成纤维细胞募集到受伤的血管壁形式首先 内膜，然后是中膜细胞层;在结构上，它们获得 微丝和细胞器与收缩，但只有在一些 是肌球蛋白优先表达。 这些细胞合成原弹性蛋白， 和弹性层（e）的形成，对于它们在 血管壁。 该申请提出，有区域和 平滑肌肌球蛋白的差异调节 微血管节段PH。假设是，在壁 重塑，中间途径的细胞迅速增加肌球蛋白 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， 高分辨率的微丝、中间丝和肌丝 免疫细胞化学; 2）通过亚细胞 通过高分辨率显微镜观察纤维和细胞器的分布; 3） 通过原位方法建立肌球蛋白和原弹性蛋白mRNA表达调节 杂交;和4）建立相对的挑战的影响 低氧对“高氧适应和断奶肺”的影响 空气 通过定义收缩和细胞骨架的组织和类型， 我们的目标是了解发生的表型转换， 在特定的血管节段的细胞中， 墙在PH

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.