Angiogenesis in the Pulmonary Microvasculature

描述（由申请人提供）：血管生成，即由已有的毛细血管形成的新血管，在许多肺部疾病的发病机制中起着重要作用，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的血管生成反应，并且在肺中启动或抑制这些反应所涉及的因素也没有很好的定义。显然，需要研究直接表征肺微血管内皮细胞（PMVECs）的血管生成反应，并确定周细胞或平滑肌细胞（SMCs）如何参与这些反应。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，结果发现了一种新的血管生成因子，鞘氨醇1-磷酸（S1P），当从血小板或其他细胞中释放时，它在血管生成中起关键作用。本研究旨在探讨S1P是一种主要的血管生成因子，它协调不同类型的细胞之间的相互作用，形成肺部的新血管。具体目标1将检查小gtpase Rho家族成员在对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，即肺新血管成熟是由PMVECs响应血管生成刺激释放的因子对平滑肌细胞的精心吸引引起的，并确定平滑肌细胞募集调节的机制。我们将提出以下假设：磷脂酰肌醇3’激酶（PI3激酶）依赖的Ak激活在内皮和SMC迁移中起着不同的作用，这种反应是血管成熟所必需的，并且在SMC中由camp依赖的蛋白激酶a动态调节。具体来说，我们将直接研究受刺激的迁移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。我们将解决中性粒细胞迁移时释放的因子在启动血管生成反应中增强中性粒细胞与内皮细胞接触的影响的假设。拟议的研究结果应该为更清楚地了解肺微血管的血管生成反应提供基础，这将对反应的治疗调节至关重要。

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.