Interactions between the guanine nucleotide exchange factor, vav2, the platelet-derived growth factor receptor-beta and phosphoinositide 3-kinase in coronary artery vascular smooth muscle cells: Functional implications in atherosclerosis

Coronary heart disease (CHD) is the major cause of mortality in the United States. Atherosclerotic plaque formation, which underlies CHD, is an inflammatory process which can result in numerous cardiovascular complications. Endothelial dysfunction or injury incites this process. Platelet-derived growth factor (PDGF) is released by platelets at the site of endothelial dysfunction which induces vascular smooth muscle cell (VSMC) proliferation, migration, and protein synthesis; phenomena involved in plaque development. PDGF activates phosphoinositide 3-kinase (PI3-K) which functions in many of these processes. The signaling protein vav2 is putatively regulated by PI3-K and acts as a guanine nucleotide exchange factor (GEF) for the Rho family of small GTPases. These GTPases can regulate cytoskeletal alterations and other processes. In these studies, it is hypothesized that vav2 interacts with the PDGF receptor-β (PDGFr-β) in coronary artery vascular smooth muscle cells (CAVSMCs) to induce cellular processes important to atherosclerosis. These studies show that vav2 interacts with the tyrosine phosphorylated PDGFr-β at Y771 of the PDGFr-β's kinase insert region through vav2's src homology 2 (SH2) domain. Vav2 is shown to be the only vav family member expressed in CAVSMCs. Upon stimulation with PDGF-BB, vav2 binds to the PDGFr-β and interacts with PI3-K's p85α subunit. This interaction occurs between vav2's N-terminal src homology 3 (SH3) domain and a proline rich (PRO) region within PI3-K p85α. Based on these studies, a model is proposed describing how PDGF may activate the GTPase rac1 through vav2. Finally, functional implications of these interactions are examined in CAVSMCs pertaining to cell proliferation, cytoskeletal alterations which may result in migration, and activation of the inflammatory transcription factor, nuclear factor-κB (NF-κB). These studies indicate that vav2 may be involved in membrane ruffling and NF-κB activation in response to PDGF-BB stimulation of CAVSMCs. Analysis of PDGF-stimulated-vav2 pathways in CAVSMCs may ultimately lead to therapeutic interventions for atherosclerosis and restenosis.