Role of the epidermal growth factor receptor in thrombin regulated vascular smooth muscle cells proliferation

Abstract

The common factor in the development of vascular diseases, such as atherosclerosis, hypertension and restenosis, is excessive accumulation and proliferation of vascular smooth muscle cells (VSMC) within inner (intima) layer of vessel wall. Thrombin, a key player in athero-coagulation maze, mediates the regulation of vascular permeability and contraction, migration and proliferation of VSMC, attracting monocytes and a variety of proinflammatory markers in atherosclerotic lesions. Thrombin exerts its effects either directly as serine proteinases and/or via activation of its G proteins coupled receptors (GPCR). It has been shown that thrombin mediates transactivation of epidermal growth factor receptor (EGFR) within the process of VSMC proliferation. EGFR transactivation process through the activation of thrombin protease activated receptor (PAR), includes a matrix metalloproteinase cleavage of membrane ligands precursors such as epidermal growth factor like growth factor that binds heparin (HB-EGF) that binds to the EGFR and activates it, leading to VSMC proliferation via downstream signaling pathways of mitogen activated protein kinase (MAPK). This review article presents review of the new literature data concerning: the role of EGFR activation in mediating the proliferative effect of thrombin in VSMC and understanding of the concept of the triple cascade of EGFR transactivation stimulated by thrombin in the mechanism of VSMC proliferation.