ENDOTHELIUM AND VESSEL MATRIX IN PULMONARY HYPERTENSION

肺动脉高压中的内皮和血管基质

• 批准号: 2292126
• 负责人: ROSEMARY CRISTIAN JONES
• 金额: $ 2.21万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-02-01 至 1998-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2292126
• 关键词: actins; animal tissue; arginine vasopressin; atrial natriuretic peptide; basement membrane; cellular pathology; elastin; endothelin; extracellular matrix; fibrous protein; gene expression; hypoxia; immunocytochemistry; myosins; nitric oxide synthase; pulmonary hypertension; serotonin; smooth muscle; vascular endothelium; vimentin

Pulmonary hypertension is an important clinical problem, either as a primary event or secondary to other injury. The walls of injured blood vessels rapidly thicken, especially those of the microvessels, where lumen restriction increases resistance to blood flow and arterial pressure. As cells proliferate in the microvessels, and as contractile cells develop from (a) interstitial fibroblasts recruited to the vessel wall or (b) vascular intermediate cells, matrix components organize these cells into intimal and medial layers. The endothelium adjacent to the developing contractile cells is an important source of agents that modify their function and proliferation. Our structural data demonstrate that basement membranes and a primary (1 degrees) elastic lamina form de novo to incorporate the fibroblasts into the vessel wall, and a secondary (2 degrees) elastic lamina forms to separate these cells from endothelium; following injury, basement membranes reform around intermediate cells, the pre-existing 1 degrees lamina thickens, and a 2 degrees lamina forms in a similar way. The endothelial cell mediators expressed in the hypertensive lung, the constituents and assembly of the laminae, and of basement membranes modulating cell movement, attachment and proliferation, are unknown. We propose that (i) the expression of endothelial-derived vasoactive mediators shifts to favor hyperplasia and contraction of the developing cells, (ii) elastin synthesis is accompanied by the differential synthesis of molecules associated with lamina formation and (iii) that the ability of cells to organize within the wall reflects expression of specific regulatory molecules in the basement membrane and extracellular matrix. As the microvessels (vessels <100 micromED) remodel, and as the walls of normally muscular vessels thicken (resistance vessels 200microm to 2000micromED) we will assess these changes by high resolution immunogold studies. We will analyze endothelial mediators, e.g., endothelin-1 and nitric oxide synthetase (AIM 1), the constituents and assembly of elastic laminae by expression of microfibrillar proteins (e.g., 31kDa microfibrillin-associated glycoprotein, a 35kDa protein and 350kDa fibrillin), tropoelastin and elastin (AIM 2), and the constituents of basement membranes (e.g., collagen type IV, laminin, tenascin, perlecan, chondroitin sulfate proteoglycan and fibronectin, AIM 3). This new data will significantly increase our understanding of the basis of cell organization in the vessel wall during the development of critical lesions in pulmonary hypertension - ones that are the structural basis of a maintained rise in pressure.

肺动脉高压是一个重要的临床问题，无论是作为 原发事件或继发于其他伤害。受伤的血墙 血管迅速增厚，特别是微血管， 管腔限制增加了血流和动脉的阻力 压力。随着细胞在微血管中增殖，以及作为收缩 细胞来源于(A)被招募到血管的间质成纤维细胞。 管壁或(B)血管中间细胞、基质成分组织 这些细胞分为内膜层和中层。邻近血管内皮细胞 发育中的收缩细胞是药剂的重要来源 修改它们的功能和增殖。我们的结构数据表明 基底膜和初级(1度)弹性膜形成 从头开始将成纤维细胞整合到血管壁中，以及 形成次级(2度)弹性板层，将这些细胞与 内皮；损伤后，基底膜在周围发生改变 中间细胞，预先存在的1度椎板加厚，并且 2度的叶片以类似的方式形成。血管内皮细胞介体 在高血压肺中表达，其成分和组装 板层和基底膜，调节细胞的运动、附着 和扩散，都是未知的。我们建议：(I)表达 内皮细胞衍生的血管活性介质转向有利于增殖和 发育中细胞的收缩，(Ii)弹性蛋白的合成 伴随着与之相关的分子的差异合成 叶片的形成和(Iii)细胞在 该壁反映了特定的调节分子在 基底膜和细胞外基质。作为微血管(血管 &lt；100 MicroMed)重塑，并作为正常肌肉血管的壁 加厚(阻力容器200微米至2000微米)我们将进行评估 这些变化是通过高分辨率免疫金研究得出的。我们将分析 血管内皮细胞介质，如内皮素-1和一氧化氮合酶 (目标1)，弹性膜的组成和组装通过表达 微纤维蛋白(例如，31 kDa的微纤维相关蛋白 糖蛋白，一种35 kDa的蛋白质和350 kDa的纤维蛋白)，原弹性蛋白和 弹性蛋白(AIM 2)和基底膜的成分(例如， IV型胶原、层粘连蛋白、肌腱蛋白、骨胶原、硫酸软骨素 蛋白多糖和纤维连接蛋白，目的3)。这一新数据将显著 增进我们对细胞组织基础的理解 肺内危重病变发生发展过程中的血管壁 高血压--是持续上升的结构性基础 在压力下。