OF WORK The migration of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of many vascular diseases. We previously showed that the regulation of PDGF-directed VSMC migration by growth status and basic FGF (FGF-2) is specifically mediated through their effects on the activation of calcium/calmodulin-dependent protein kinase II (CamKII). Our current work is focussed on identifying the intracellular targets for CamKII, its upstream regulation, and its unique role in beta3 integrin-mediated signaling. We have shown that occupancy of beta3 integrin complexes is required for CamKII activation and VSMC migration and that signaling from beta3 integrins to CamKII occurs through a FGF2-dependent signaling pathway. suggesting that occupancy of beta3-containing integrins in VSMCs not only regulates migration by facilitating CamKII activation. In addition, we have shown that antibodies against thrombospondin (TSP) and integrin-associated protein (IAP), which is the major cellular binding site for the C-terminal binding domain (CBD) of TSP, also block migration though the beta3 integrin- and CamKII- dependent pathways. Interestingly, the migration of VSMC cell lines isolated from old animals is not affected by beta3 integrin blockade. These older cells apparently utilize non-integrin signaling pathways for migration and may be deficient in """"""""functional"""""""" beta3 integrins or TSP production. These results represent the first demonstration of how outside-in signaling by beta3-containing integrins modulates a specific growth-factor stimulated signaling pathway. They identify a unique intracellular signalling network in VSMCs that is triggered by chemoattractant recognition and modulated by growth status, secretion of growth factors and ECM components, and ECM-VSMC interactions. They also identify an important difference between VSMCs isolated from animals of different ages that could account for the greater responsiveness of older vessels to injury.
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