Inhibition of Mitogen-Activated Protein Kinases (MAPKs) as a Strategy to Prevent Intimal Hyperplasia Following Cardiovascular Interventions

Upon injury, blood vessels undergo a significant remodeling characterized by intimal damage and dedifferentiation of medial smooth muscle cells. Normally quiescent medial cells lose their contractile phenotype and begin to proliferate, migrate, and secrete abundant extracellular matrix. The resulting neointima formation, also referred to as intimal hyperplasia, precedes atherosclerosis of the vascular conduits. Restenosis greatly limits the success of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting (CABG), two common procedures widely used to restore circulation in occluded vascular districts. Growth factors, cytokines, inflammatory mediators, and oxidative and shear stress are among the culprits that initiate this process. More recent studies have been directed towards the intracellular sensors of these stimuli in the hope of discovering the common mechanisms that control the response to injury. A group of enzymes called mitogen-activated protein kinases (MAPKs) play a central role in relaying extracellular stimuli to the cellular core, the nucleus. The discovery that MAPK intracellular signaling pathways control processes as diverse as cell proliferation, migration, and survival via fine modulation of gene expression has prompted a number of studies on MAPK involvement in the response to vascular injury. Here we review the studies that characterized MAPK activation upon arterial or vein graft injury and its involvement in vascular remodeling. The experimental findings indicate that the MAPK signaling pathways are suitable targets for novel therapies to prevent restenosis of blood conduits and extend their life span.