The aggregation of platelets at sites of vascular injury causes release of a platelet protein which stimulates the growth of vascular smooth muscle cells and elicits a variety of metabolic responses. This protein, platelet-derived growth factor (PDGF), is thought to play a role in the proliferative vascular lesions of atherosclerosis. It also stimulates the release of prostacycline from vascular smooth muscle cells. We have recently found that in addition to its effects on smooth muscle cells, PDGF is a very potent chemoattractant for human polymorphonuclear leukocytes. Presumably this chemotactic effect is important in the inflammatory response elicited by platelets at the site of vascular damage. Our goal is to investigate the first steps in the action of PDGF. Specifically, we will study the interaction of PDGF with its receptor sites on vascular smooth muscle cells. For these studies we will radioactively label PDGF and will use radioligand binding techniques to identify the receptor sites. We will document that the binding sites have the appropriate affinity, specificity, and kinetics expected of PDGF receptors. We will then use these methods to study the regulation of PDGF receptors by a variety of modulatory influences including alterations in cell density, chronic exposure to PDGF, and pre-treatment with serotonin, a potentiator of PDGF activity. Using PDGF coupled to ferritin, we will localize PDGF receptors by electron microscopy and will investigate whether PDGF receptors on human leukocytes will allow us to investigate the possibility that there are generalized alterations of PDGF receptors in disease states such as atherosclerosis in which there may be an abnormal proliferative response to PDGF. These studies should provide insight into the mechanism of action of PDGF as a mitogenic and inflammatory agent and should enhance our undrestanding of the effects of platelet products on blood vessels.
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