Abstract
Increased vascular smooth muscle cell (VSMC) proliferation contributes towards restenosis after angioplasty, vein graft intimal thickening and atherogenesis. The second messenger 3′ 5′ cyclic adenosine monophosphate (cAMP) plays an important role in maintaining VSMC quiescence in healthy vessels and repressing VSMC proliferation during resolution of vascular injury. Although the anti-mitogenic properties of cAMP in VSMC have been recognised for many years, it is only recently that we gained a detailed understanding of the underlying signalling mechanisms. Stimuli that elevate cAMP in VSMC inhibit G1-S phase cell cycle progression by inhibiting expression of cyclins and preventing S-Phase Kinase Associated Protein-2 (Skp2-mediated degradation of cyclin-dependent kinase inhibitors. Early studies implicated inhibition of MAPK signalling, although this does not fully explain the anti-mitogenic effects of cAMP. The cAMP effectors, Protein Kinase A (PKA) and Exchange Protein Activated by cAMP (EPAC) act together to inhibit VSMC proliferation by inducing Cyclic-AMP Response Element Binding protein (CREB) activity and inhibiting members of the RhoGTPases, which results in remodelling of the actin cytoskeleton. Cyclic-AMP induced actin remodelling controls proliferation by modulating the activity of Serum Response Factor (SRF) and TEA Domain Transcription Factors (TEAD), which regulate expression of genes required for proliferation. Here we review recent research characterising these mechanisms, highlighting novel drug targets that may allow the anti-mitogenic properties of cAMP to be harnessed therapeutically to limit restenosis.
Highlights
Vascular responses to injury include development of atherosclerotic plaques in response to cardiovascular risk factors, restenotic lesions after angioplasty, or intima formation during late vein graft failure, all of which are associated with increased rates of vascular smooth muscle cell (VSMC)proliferation
We are beginning to understand that remodelling of the actin cytoskeleton plays a central role in the complex cyclic adenosine monophosphate (cAMP) signalling mechanisms that control VSMC proliferation
Actin cytoskeleton organisation is promoted by a diverse set of signals from the local microenvironment, including growth factors, inflammatory cytokines, the composition and mechanical properties of the ECM, and mitogenic GPCR ligands
Summary
Vascular responses to injury include development of atherosclerotic plaques in response to cardiovascular risk factors, restenotic lesions after angioplasty, or intima formation during late vein graft failure, all of which are associated with increased rates of vascular smooth muscle cell (VSMC). Defects in this repair capacity, due to replicative senescence or increase apoptosis, is associated with medial thinning and aneurysm formation [4,5] This capacity has no doubt evolved to compensate for traumatic injury, but its importance has recently become central in clinical cardiology and vascular surgery owing to its role in atherosclerosis and the two effective interventions developed to treat symptomatic atherosclerotic disease, angioplasty and venous by-pass graft surgery [6]. The primary purpose of VSMC proliferation is vascular repair after which it is essential that proliferation rates return to their normal low levels, an event that is associated with resolution of inflammation and re-establishment of normal endothelial function
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