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 主要事件或继发于其他损伤。受伤的血墙 血管迅速扩张，尤其是微血管， 管腔限制增加了对血流和动脉的阻力 压力当细胞在微血管中增殖， 细胞从（a）募集到血管的间质成纤维细胞发育 壁或（B）维管中间细胞，基质成分组织 将这些细胞分化为内膜层和中层。内皮细胞邻近 发育中的收缩细胞是一种重要的物质来源， 改变它们的功能和增殖。我们的结构数据表明 基底膜和初级（1度）弹性膜形成 从头将成纤维细胞掺入血管壁，以及 次级（2度）弹性膜形成，以将这些细胞与 损伤后，基底膜改革周围 中间细胞，预先存在的1度层增厚， 2度叶片以类似的方式形成。内皮细胞介质 表达在高血压肺，组成和组装的 板层和调节细胞运动、附着的基底膜 和扩散，是未知的。我们建议：（i） 内皮源性血管活性介质转变为有利于增生， 收缩的发展中的细胞，（ii）弹性蛋白的合成是 伴随着分子的差异合成， 纤层形成和（iii）细胞在内部组织能力 细胞壁反映了细胞内特定调节分子的表达， 基底膜和细胞外基质。作为微血管（血管 <100微米）重塑，并作为正常肌肉血管的壁 我们将评估血管阻力（200微米至2000微米） 这些变化通过高分辨率免疫金研究。我们将分析 内皮介质，例如，内皮素-1和一氧化氮合成酶 (AIM 1）弹性层的组成和组装 微纤维蛋白（例如，31 kDa微原纤蛋白相关 糖蛋白，35 kDa蛋白和350 kDa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、腱生蛋白、串珠素、硫酸软骨素 蛋白聚糖和纤连蛋白，AIM 3）。这些新数据将大大 增加我们对细胞组织基础的理解， 血管壁的发展过程中的关键病变在肺 高血压-那些是持续上升的结构基础 压力。