Novel insights into the role of glucose metabolism in regulating vascular smooth muscle cell phenotype and proliferative capacity

Abnormal vascular smooth muscle cell (VSMC) proliferation is a hallmark in the pathogenesis of vascular disease. Atherosclerosis or arterial damage due to angioplasty results in exposure of medial smooth muscle cells to growth factors such as platelet‐derived growth factor‐BB (PDGF‐BB); these growth factors promote a cellular phenotype switch from a contractile phenotype to a proliferative, synthetic phenotype. However, the mechanisms by which growth factors cause this phenotype switch remain unclear. We hypothesized that glucose metabolism is a primary regulator of PDGF‐BB‐induced VSMC phenotype and proliferative capacity. Treatment of VSMCs with PDGF‐BB (10 ng/ml) significantly increased glycolytic flux, cell proliferation, and the expression of osteopontin and vimentin—both of which are markers of the synthetic VSMC phenotype. Inhibition of glycolysis with koningic acid, an irreversible inhibitor of GAPDH, did not cause cell death, but decreased proliferation and prevented the upregulation of osteopontin and vimentin. Koningic acid treatment significantly increased the levels of proteins modified by O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) but did not affect PDGF‐BB‐induced phosphorylation of Erk1/2 or Akt. Treatment of VSMCs with inhibitors of the O‐GlcNAcase enzyme, PUGNAc or Thiamet‐G, increased protein O‐GlcNAcylation and maintained cells in a quiescent, contractile phenotype despite their stimulation with PDGF‐BB. These data suggest that glucose metabolism regulates cell growth and that the hexosamine biosynthetic pathway is fundamental for maintaining a quiescent phenotype. Understanding how cellular energetics integrate with glucose‐derived metabolic signaling should aid in developing therapeutic strategies to prevent VSMC hyperproliferation, especially in the context of metabolic diseases such as diabetes.