Abstract 769: SERCA2a Controls Vascular Smooth Muscle Cell Proliferation in Human Arteries
Background: Coronary restenosis, a major complication of percutaneous balloon angioplasty, results mainly from the proliferation of vascular smooth muscle cells (VSMC). The goals of this study were to determine whether in human arteries 1) proliferation is associated with changes in the expression of Ca2+ handling proteins, and 2) gene transfer of the sarco/endoplasmic reticulum calcium ATPase, SERCA2a, can prevent VSMC proliferation.
Methods and results: Coronary arteries (CA) from human explanted hearts and left internal mammary arteries (MA) were obtained at the time of aorto-coronary bypass surgeries. In atherosclerotic CA, SERCA2a and the ryanodine receptor (RyR2) were expressed only in VSMC from the media but not in the neointima. SERCA2a was absent from proliferating human VSMC in vitro and SERCA2a gene transfer inhibited proliferation through the calcineurin/NFAT pathway. Expression of SERCA2a or VIVIT was associated with downregulation of cell cycle controlling proteins cyclin D1 and Erg-1. To confirm the in vitro results, we used an ex-vivo model of injured human MA kept 2 weeks in organ culture under constant pressure and flow. Adenovirus gene transfer of SERCA2a significantly (p<0.005) reduced vascular remodelling and neointima formation in such arteries (intima/media ratio was 0.07 ± 0.01 vs 0.43 ± 0.05 in βGal-infected arteries).
Conclusions. In human vessels, SERCA2a has direct effects on the proliferation of VSMC and neointima formation via the transcription factor NFAT. These findings could have potential implications for treatment of pathological restenosis.