Angiogenesis in the Pulmonary Microvasculature

肺微血管中的血管生成

• 批准号: 6760094
• 负责人: Rafat Ali Siddiqui
• 金额: $ 24.58万
• 依托单位: INDIANA UNIVERSITY HEALTH, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-01 至 2005-02-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6760094
• 关键词: angiogenesis; angiogenesis factor; biological signal transduction; cell membrane; clinical research; enzyme mechanism; guanine nucleotide binding protein; guanosinetriphosphatases; human subject; hydrolase; immunoprecipitation; inflammation; lung; neutrophil; phlebotomy; phosphatidylinositol 3 kinase; phospholipase D; pulmonary veins; tissue /cell culture; transfection; vascular endothelium; vascular smooth muscle

DESCRIPTION (provided by applicant): Angiogenesis, the formation of new blood vessels from pre-existing capillaries, plays an important role in the pathogenesis of many pulmonary diseases, including infection, inflammation, thromboembolism, tissue injury, and cancer. However, few studies have directly examined angiogenic responses of pulmonary microvasculature, and the factors involved in initiating or inhibiting these responses in the lung are not well defined. Clearly, studies are needed to directly characterize angiogenic responses of pulmonary microvascular endothelial cells (PMVECs) and to determine how pericytes or smooth muscle cells (SMCs) contribute to these responses. Our previous investigations, designed to determine how interactions of endothelial cells with circulating blood cells influence pathologic and homeostatic processes in the lung, resulted in the identification of a novel angiogenic factor, sphingosine 1-phosphate (S1P), that, when released from platelets or other cells, plays a key role in angiogenesis. The present investigation is designed to explore the hypothesis that S1P is a major angiogenic factor that coordinates the interactions among the different types of cells that form new blood vessels in the lung. Specific aim 1 will examine the role of members of the Rho family of small GTPases in angiogenic responses to protein and lipid angiogenic factors and define the mechanisms leading to their activation. Specific aim 2 will explore the possibility, suggested by our preliminary data, that pulmonary neovessel maturation results from the orchestrated attraction of smooth muscle cells by factors released from PMVECs responding to angiogenic stimuli and define the mechanisms involved in regulation of smooth muscle cell recruitment. We will address the hypothesis that phosphatidylinositol 3' kinase (PI3 kinase)-dependent activation of Ak, is differentially involved in endothelial and SMC migration, that this response is necessary for vascular maturation and that it is dynamically regulated in SMC by cAMP-dependent protein kinase A. Specific aim 3 will address the potential role of angiogenesis in the pathogenesis of pulmonary inflammatory disease. Specifically, we will directly examine the influence of stimulated, migrating neutrophils and factors released by these cells on specific facets of PMVEC angiogenic responses. We will address the hypothesis that factors released when neutrophils migrate potentiate the influence of neutrophil-endothelial cell contact in initiating angiogenic responses. The results of the proposed investigation should provide a foundation for a clearer understanding of angiogenic responses of the pulmonary microvasculature, an understanding that will be critical for therapeutic regulation of the response.

描述（由申请人提供）：血管生成，即从预先存在的毛细血管形成新血管，在许多肺部疾病的发病机制中发挥着重要作用，包括感染、炎症、血栓栓塞、组织损伤和癌症。 然而，很少有研究直接检查肺微血管系统的血管生成反应，并且参与启动或抑制肺部这些反应的因素尚不清楚。显然，需要研究直接表征肺微血管内皮细胞（PMVEC）的血管生成反应，并确定周细胞或平滑肌细胞（SMC）如何促进这些反应。 我们之前的研究旨在确定内皮细胞与循环血细胞的相互作用如何影响肺部的病理和稳态过程，结果发现了一种新型血管生成因子——鞘氨醇 1-磷酸 (S1P)，当它从血小板或其他细胞释放时，在血管生成中发挥关键作用。 本研究旨在探索这样的假设：S1P 是一种主要的血管生成因子，可协调肺部形成新血管的不同类型细胞之间的相互作用。 具体目标 1 将检查小 GTP 酶 Rho 家族成员在蛋白质和脂质血管生成因子的血管生成反应中的作用，并确定导致其激活的机制。 具体目标 2 将探讨我们的初步数据表明的可能性，即肺新生血管成熟是由于 PMVEC 响应血管生成刺激而释放的因子对平滑肌细胞进行精心设计的吸引所致，并确定参与调节平滑肌细胞募集的机制。 我们将提出这样的假设：磷脂酰肌醇 3' 激酶（PI3 激酶）依赖性 Ak 激活不同程度地参与内皮和 SMC 迁移，这种反应对于血管成熟是必需的，并且它在 SMC 中受到 cAMP 依赖性蛋白激酶 A 的动态调节。具体目标 3 将解决血管生成在肺部炎症性疾病发病机制中的潜在作用。 具体来说，我们将直接检查受刺激、迁移的中性粒细胞和这些细胞释放的因子对 PMVEC 血管生成反应的特定方面的影响。 我们将提出这样的假设：中性粒细胞迁移时释放的因子增强了中性粒细胞-内皮细胞接触对启动血管生成反应的影响。 拟议的研究结果应该为更清楚地了解肺微血管系统的血管生成反应提供基础，这种理解对于反应的治疗调节至关重要。