Angiogenesis in the Pulmonary Microvasculature

描述(申请人提供)：血管生成，即从原有的毛细血管形成新的血管，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、血栓栓塞症、组织损伤和癌症。然而，很少有研究直接研究肺微血管的血管生成反应，在肺内启动或抑制这些反应的因素也不是很清楚。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(SMC)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内的病理和动态平衡过程，结果发现了一种新的血管生成因子-1-磷酸鞘氨醇(S1P)，当它从血小板或其他细胞中释放出来时，在血管生成中发挥关键作用。目前的研究旨在探索一种假设，即S1P是一种主要的血管生成因子，它协调形成肺内新血管的不同类型细胞之间的相互作用。具体目标1将研究Rho家族小GTP酶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，并确定导致它们激活的机制。具体目标2将探讨我们的初步数据提示的可能性，肺新生血管成熟是由于PMVECs对血管生成刺激的反应所释放的因子协调地吸引平滑肌细胞，并确定参与调节平滑肌细胞募集的机制。我们将提出一种假设，即依赖于磷脂酰肌醇3‘激酶(PI3激酶)的AK的激活与内皮和SMC的迁移有关，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。具体地说，我们将直接检查刺激的、迁移的中性粒细胞以及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。我们将提出一种假设，即中性粒细胞迁移时释放的因子加强了中性粒细胞-内皮细胞接触在启动血管生成反应中的影响。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，这一理解将对治疗调节反应至关重要。

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.