Homocysteine activates vascular smooth muscle cells by DNA demethylation of platelet-derived growth factor in endothelial cells

J Mol Cell Cardiol. 2012 Oct;53(4):487-96. doi: 10.1016/j.yjmcc.2012.07.010. Epub 2012 Jul 31.


Hyperhomocysteinemia (HHcy), as an independent risk factor of atherosclerosis, facilitates endothelial dysfunction and activation of vascular smooth muscle cells (VSMCs). However, little is known about the crosstalk between endothelial cells (ECs) and VSMCs under HHcy. We investigated whether homocysteine (Hcy) activates VSMCs by aberrant secretion of mitogen platelet-derived growth factors (PDGFs) from ECs in human and in mice. In this study, we found that increased Hcy level did not affect VSMC activity in 24 hrs until the concentration reached 500 μM. In contrast, Hcy at 100 μM significantly promoted proliferation and migration of VSMCs co-cultured with human ECs. This effect was partially reversed by pretreatment with a PDGF receptor inhibitor. Hcy concentration-dependently upregulated the mRNA level of PDGF-A, -C and -D but not PDGF-B in ECs. Hcy reduced the expression and activity of DNA methyltransferase 1, demethylation of PDGF-A, -C and -D promoters and enhanced the binding activity of transcriptional factor SP-1 to the promoter. Hcy upregulation of PDGF was confirmed in the aortic intima of mice with HHcy. Multivariate regression analysis revealed HHcy was a predictor of increased serum PDGF level in patients. Thus, Hcy upregulates PDGF level via DNA demethylation in ECs, affects cross-talk between ECs and VSMCs and leads to VSMC activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Atherosclerosis
  • Cell Proliferation
  • Cells, Cultured
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation*
  • Endothelium, Vascular / metabolism*
  • Homocysteine / metabolism*
  • Human Umbilical Vein Endothelial Cells / metabolism*
  • Humans
  • Hyperhomocysteinemia / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Muscle, Smooth, Vascular / metabolism*
  • Platelet-Derived Growth Factor / metabolism*
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering
  • Rats
  • Signal Transduction
  • Sp1 Transcription Factor / genetics
  • Sp1 Transcription Factor / metabolism
  • Tunica Intima / metabolism


  • Platelet-Derived Growth Factor
  • RNA, Small Interfering
  • Sp1 Transcription Factor
  • Homocysteine
  • DNA (Cytosine-5-)-Methyltransferase 1
  • DNA (Cytosine-5-)-Methyltransferases