Both thrombotic and inflammatory mediators contribute to the development of vascular disease. Blood platelets, which are known to play an essential role in ischemic heart disease and stroke by contributing to acute thrombotic events, also release potent inflammatory agents within the vasculature. Lysophosphatidic acid (LPA) is a bioactive lipid mediator that is produced by platelets and found in abundance in human atherosclerotic plaques. LPA stimulates platelets, leukocytes, endothelial cells, and smooth muscle cells by acting through specific cell surface G-protein coupled receptors (LPA1-3) to regulate cell growth, differentiation, survival, motility, and contractile activity. LPA may also be an agonist for the nuclear peroxisome proliferator-activated receptor gamma (PPARgamma). Thus, LPA is poised to serve as a key mediator of both inflammatory and thrombotic responses and to be a pathophysiologic regulator of vascular cell function. The objective of this application is to determine the physiologic contribution of LPA to events that are relevant to atherothrombotic vascular disease and to identify the LPA receptor(s) involved. Our central hypothesis is that LPA generated, in part, by activated platelets stimulates phenotypic modulation of medial SMCs and that these responses regulate vascular tone and contribute to the development of intimal hyperplasia after arterial injury and in the setting of atherosclerosis. We propose to test our hypothesis by integrating cellular, pharmacologic and functional genomics approaches in the following three specific aims (1) establish a pathologic role for LPA in the vascular response to injury; (2) identify LPA receptors that mediate phentypic modulation of cultured vascular SMCs; (3) Identify the role of LPA receptors in the regulation of vascular tone. To accomplish our goals, we will use mice deficient in the three known G-protein coupled LPA receptors (LPA1-3), novel pharmacologic sub-type selective agonists and agonistists of LPA1-3, and mice with a PPARgamma mutation that abolishes ligand binding. Our results will provide specific insights into the role of LPA signaling pathways in vascular physiology and pathology and may provide novels targets for the treatment and prevention of atherothrombotic disorders.
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