The migration of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of many vascular diseases. We have previously shown that VSMC migration in response to PDGF is suppressed in differentiated VSMCs due to the failure of these cells to activate calcium/calmodulin-dependent protein kinase II (CamKII) in response to the chemoattractant, platelet derived growth factor BB (PDGF BB). This was convincingly demonstrated by overexpressing constitutively activated CamKII in VSMCs and showing that these cells migrate toward PDGF even when they are induced to differentiate. Our current work is focussed on the regulation of this signaling pathway by the growth factors PDGF AA and bFGF and by the cell interactions with the extracellular matrix. We have shown that production of bFGF by VMSCs is required for PDGF-induced migration, while the inclusion of PDGF AA inhibits such migration. Both of these factors mediate their effects by influencing CamKII activation (bFGF stimulates, while PDGF AA inhibits PDGF-induced CamKII) and this requirement or inhibition can be overridden by forced expression of activated CamKII. Occupancy of both beta1 and beta3 integrins is also required for VSMC migration. The nature of that requirement is through their ability to modify intracellular signaling initiated by chemoattractants rather than cell attachment or detachment. We have shown that blockade of beta3 integrins, such as alphav beta33 integrin, inhibits migration and leads to a reduction in CamKII activation by the chemoattractant. This inhibition of migration is overridden by forced expression of activated CamKII delivered by a recombinant adenoviral vector. In contrast, the inhibition of migration caused by ?1 integrin blockade is not overridden by CamKII and may involve activation of the MAPK pathway. The beta3-mediated effect occurs through occupancy of integrin receptors with extracellular matrix components secreted by chemoattractant-stimulated VSMCs (e.g. thrombospondin and osteopontin) rather than those already present in the extracellular matrix. Overall, these results identify a unique intracellular signalling network in VSMCs that is triggered by chemoattractant recognition and modulated by growth factors secreted by VMSCs or adjacent cells and by changes in extracellular matrix composition.
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