Most failures in vascular surgery are caused by acute platelet-dominated thrombosis or later by intimal hyperplasia. Both of these pathological processes depend upon the actions of integrins, a family of adhesive receptors expressed on vascular cells. Recent data from the laboratories of Dr. Michael Sobel and others suggest that heparin's non-anticoagulant effects on vascular cells may be integrin-mediated. For example, these effects include heparin inhibition of vascular smooth muscle cell (VSMC) migration, as well as the direct non-immune effects of heparin on platelet function. The long-range goals of this investigation are to elucidate how heparin modulates integrin signaling and function in platelets and VSMC. Our first specific aim 1 will seek to define the effects of heparin on early, upstream signaling events, through the measurement of Ligand Induced Binding Sites, and early protein phosphorylation events in human platelets - a model system for study of integrin signaling. In the second specific aim, heparin modulation of integrin function in the setting of cellular migration will be examined. By using K562 cells expressing normal human integrins and through the study of VSMCs with different adhesive matrices and stimuli, the precise heparin interactions with varied integrins and their subunits will be defined. These investigations should lead to critical new insights into the fundamental roles of heparins and integrins in vascular surgery.
