Regulation of vascular smooth muscle cell differentiation

Vascular smooth muscle cell (VSMC) phenotypic markers. Immunohistochemical staining of human VSMC with anticalponin antibody treated with ethanol (left) or 20 nM rapamycin (right) for 48 hours in 2.5% calf serum. Right, Human VSMC grown in monolayers dedifferentiate to a synthetic phenotype. Left, The addition of rapamycin causes differentiation of VSMC.) The differentiation state of VSMCs is highly plastic and dependent on integration of multiple external factors. This figure summarizes the major markers during VSMC phenotypic modulation. ECM, Extracellular matrix; MMP, matrix metalloproteinase; SM-MHC,smooth muscle-myosin heavy chain; TIMP, tissue inhibitor of matrix metalloproteinase.

Rapamycin induces vascular smooth muscle cell (VSMC) contractile protein expression. A, Immunofluorescent anticalponin staining of bovine VSMC treated with ethanol (left) or 20 nM rapamycin (right) for 48 hours in 2.5% calf serum. B, Top panel, Antismooth muscle heavy chain (SM-MHC) SM2 western blot of rat VSMC cultured with ethanol or 20 nM rapamycin in 2.5% serum. Bottom panel, Anticalponin western blot of bovine VSMC cultured with ethanol or 20 nM rapamycin in 2.5% serum. C, Anticalponin Western blot of bovine VSMC in the presence of vehicle or indicated drugs for 48 hours. Rap, 20 nmol/L rapamycin; LY, 10 μmol/L LY294002; SB, 10 μmol/L SB203580; UO, 5 μmol/L UO126. (Data from Martin KA, Rzucidlo EM, Merenick BL, et al, The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol 2004;286:C507-17.)

Our current model of signaling pathways that regulate vascular smooth muscle cell (VSMC) differentiation. Rapamycin and a soluble endothelial cell mediator regulate VSMC differentiation through a feedback regulation of the insulin growth factor-I (IGF-I)/insulin receptor substrate-1/phosphoinositide 3-kinase (PI3K)/AKT pathway. Prostacyclin activation of the effector pathway Gα_s/adenylyl cyclase/cyclic adenosine monophosphate (cAMP) /protein kinase A (PKA) induces VSMC differentiation. Statins induce VSMC differentiation through a yet undetermined pathway. mTOR, Mammalian target of rapamycin; S6K1, S6 kinase 1.