Beyond Phosphorylation

Abstract

The vasculature is composed of endothelial cells, vascular smooth muscle cells (VSMCs), fibroblasts, and immune cells with closely integrated functions. It is exposed to a variable environment of pulsatile flow and changing blood pressure, plus fluctuations in nutrient, oxidative, and cytokine stress. Adaptation to this changing environment is critical for sustained vascular health. VSMCs undergo a phenotype change in response to vascular injury, including migration, proliferation, and matrix production, also known as VSMC activation or phenotypic modulation. VSMC activation contributes to the progression of atherosclerosis and postangioplasty restenosis. Understanding the endogenous regulators of vascular plasticity and adaptation has revealed potential targets for pharmacological intervention to prevent vascular stenosis. For example, Ross established cAMP as a critical signaling pathway for the maintenance of VSMC quiescence.1 Since that time, agents that increase cAMP, such as phosphodiesterase inhibitors, have demonstrated usefulness as vasodilators, with clinical implications for pulmonary hypertension.2,3 Intracellular accumulation of cAMP signals to protein kinase A and the cAMP-responsive Rap1 guanine nucleotide exchange factor, Epac; simultaneous activation of both of these pathways by cAMP is essential for the antiproliferative impact on VSMCs.3,4 …