Angiogenesis in the Pulmonary Microvasculature

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起重要作用，包括感染、炎症、血栓栓塞、组织损伤和癌症。 然而，很少有研究直接研究肺微血管的血管生成反应，并且启动或抑制肺中这些反应的因素也没有很好地定义。显然，研究需要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。 我们以前的调查，旨在确定如何与循环血细胞的内皮细胞的相互作用，影响病理和稳态过程中的肺，导致在一个新的血管生成因子，鞘氨醇1-磷酸（S1 P）的鉴定，当从血小板或其他细胞释放，在血管生成中起着关键作用。 本研究旨在探讨S1 P是一种主要的血管生成因子的假设，该因子协调了在肺中形成新血管的不同类型细胞之间的相互作用。 具体目标1将研究小GTP酶的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将探讨的可能性，我们的初步数据表明，肺新生血管成熟的结果从协调的吸引平滑肌细胞的因子释放的PMVEC响应血管生成的刺激和定义的机制参与调节平滑肌细胞的招聘。 我们将阐明这样的假设，即Ak的磷脂酰肌醇3'激酶（PI 3激酶）依赖性激活与内皮细胞和SMC迁移有关，这种反应是血管成熟所必需的，并且在SMC中受cAMP依赖性蛋白激酶A的动态调节。 具体目标3将阐述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，我们将直接研究刺激，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。 我们将讨论这一假设，即中性粒细胞迁移时释放的因子增强了嗜中性粒细胞-内皮细胞接触在启动血管生成反应中的影响。 拟议的调查结果应提供一个基础，更清楚地了解肺微血管的血管生成反应，理解将是至关重要的治疗调节的反应。

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.