VASCULAR CELL PHENOTYPES IN PULMONARY HYPERTENSION

肺动脉高压的血管细胞表型

• 批准号: 2222453
• 负责人: ROSEMARY CRISTIAN JONES
• 金额: $ 26.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-09-30 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2222453
• 关键词: actins; cell type; cytoskeletal proteins; fibroblasts; genetic regulation; genetic transcription; immunocytochemistry; immunoelectron microscopy; immunofluorescence technique; in situ hybridization; intermediate filaments; laboratory rat; microcirculation; myosins; nucleic acid probes; phenotype; pulmonary hypertension; respiratory hypoxia; transmission electron microscopy; vascular endothelium; vascular smooth muscle; wound healing

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.

描述：（根据申请人的摘要和特定目的改编。） 受伤的血管的壁迅速在肺中增厚 高血压（pH），尤其是微血管的高血压（pH） 限制会增加肺血管阻力和压力。 作为细胞 肥大和增殖狭窄的容器腔，细胞和基质 组件被组织成新的内膜，内侧和外在层， 和新的收缩细胞在正常的非肌肉段中发展（即 新肌肉化）。 丝状蛋白的表达负责 这种生长模式伴随的血管细胞分化 保持未表征。 结果表明中间细胞和迁移 首先招募到受伤的容器壁形式的间质成纤维细胞 内侧细胞层；从结构上讲，它们获得了 与收缩相关的微丝和细胞器，但仅在某些 是肌球蛋白优先表达。 这些细胞的Tropoelastin合成， 和弹性薄片（E）形成，对他们的组织至关重要 船墙。 申请提出有区域性和 平滑肌肌球蛋白在细胞中的差异调节 pH中的微血管段。 假设是在墙上 重塑，中间途径的细胞迅速增加肌球蛋白 表达成纤维细胞途径的表达 细胞骨架蛋白。 具体目的是：1）确定 通过分析肌动蛋白的表达来分布细丝蛋白 通过高分辨率的微丝，中间细丝和肌膜 免疫细胞化学； 2）通过亚细胞定义细胞晶格 通过高分辨率显微镜分布细丝和细胞器； 3） 通过原位建立肌球蛋白和肌动蛋白mRNA表达的调节 杂交； 4）建立相对挑战的影响 通过回到呼吸，在“适应高氧和断奶的肺”上缺氧 空气。 通过定义收缩和细胞骨架的组织和类型 细丝，目标是了解发生的表型切换 在特定血管段的细胞中重塑血管时 pH中的墙。