LOW-DOSE VALPROIC ACID ENHANCES ENDOTHELIAL CELL PROLIFERATION AND ACCELERATES RE-ENDOTHLIALIZATION IN BALLOON-INJURED RAT CAROTID ARTERY

Re-endothelialization after stent implantation and vascular injury is a critical step in the process of vascular healing. Proliferation of human umbilical vein endothelial cells (HUVECs) is a major factor influencing the induction of re-endothelialization. Valproic acid (VPA) is a widely used anti-epileptic drug. VPA was recently shown to modulate expression of various genes involved in angiogenic activity. However, accumulating evidence suggests that significant dose-dependent antiproliferative effects of VPA can occur and partial cytotoxic effects may restrict the use of VPA to local high-dose (≥ 1mM) devices such as a drug eluting stent. Therefore, we evaluated the effects of low-dose VPA on proliferation of HUVECs and vascular smooth muscle cells (VSMCs) in-vitro and neointima formation in balloon-injured rat carotid arteries in-vivo. Treatment of HUVECs with low-dose VPA (≤ 1mM) promoted proliferation, whereas VSMCs were not affected. Particularly, VPA 100 nM and 100 μM promoted endothelial proliferation by 151.41 ± 15.40% and 163.28 ± 4.82%, respectively, compared with the control group. These changes were preceded by increased expression of extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3K)/Akt (Akt), and endothelial nitric-oxide synthase (eNOS). VPA was also found to accelerate re-endothelialization, thereby inhibiting neointima formation in balloon-injured rat carotid arteries. VPA reduces neointima formation by promoting re-endothelialization. The results of this study have significant implications for treating restenosis following revascularization.