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.
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