Coronary intervention with balloon injury provokes proliferation of VSMCs resulting in neointimal hyperplasia. Swine model of coronary restenosis is widely recognized that accurately mimics the proliferative component of human restenosis. We observed significant neointimal development in all coronary PI-103 citations arteries following balloon injury. TNF-a, a cytokine secreted by VSMC in the neointima, plays an important role in the pathogenesis of restenosis. All post-angioplasty coronary arteries showed increased TNF-a expression in neointimal area. Interestingly, VDR expression was significantly decreased in proliferating SMCs of neointimal lesion. Both in-vitro and in-vivo studies have shown that biological response to 1, 25 D2 is directly related to the VDR content of target tissue. Thus, the regulation of VDR expression is vital for the hormonal actions of vitamin D. Deficiency of vitamin D has been linked with increased risk of cardiovascular disease-related mortalities including hypertension, congestive heart failure, peripheral arterial disease, and myocardial infarction. However, most of these evidence come from epidemiological studies. Recent studies have also shown that vitamin D deficiency may be associated with several other indices of vascular function including development and progression of atherosclerosis. However, the exact mechanism by which vitamin D might influence the development, progression and prognosis of CAD has not yet been elucidated. Additionally, it is uncertain as to what stage of CAD vitamin D may have its beneficial effects. In this study, we investigated the invivo effects of vitamin D status on the development of neointimal hyperplasia following coronary intervention. Results from our study demonstrated that the development of neointimal hyperplasia after balloon injury to coronary artery negatively correlates with serum vitamin D status. The number of PCNA-positive cells in neointimal region was also significantly reduced, suggesting invivo antiproliferative effect of vitamin D. These in vivo data were further confirmed in cultured PCASMCs in vitro. We found that VDR is present in PCASMCs at both transcriptional and translational level and stimulation of the cells with calcitriol increases VDR expression in a dose-dependent manner. These finding are in conformity with previous studies where stimulation of rat or rabbit VSMCs to calcitriol up-regulated VDR expression, suggesting that the effect of calcitriol on VSMCs are mediated through VDR. The direct effect of calcitriol on the proliferation of VSMCs is not clear. In an in-vitro study calcitriol increased the thymidine incorporation and modulated the growth of quiescent rat VSMCs similar to a-thrombin or PDGF. However, in striking contrast, this study also showed that calcitriol diminished the mitogenic response to thrombin by as much as 50% in nonquiescent rat VSMCs. We observed potent anti-proliferative effects of calcitriol in PCASMCs. Interestingly calcitriol stimulation had no effect on apoptosis in PCASMCS. These findings support the study by Wu-Wong and colleagues which showed that calcitriol inhibit proliferation in human coronary artery SMCs in a dose-dependent manner. PDGF-BB plays a pivotal role in VSMC proliferation and migration. In this study, PDGF-BB- induced proliferation of PCASMCs was inhibited by calcitriol treatment. Such an effect of calcitriol was abolished by the specific knockdown of VDR in PCASMCs, suggesting that the growth inhibitory effect of calcitriol is mediated through VDR. In an earlier study, TNF-a inhibited calcitriol-induced VDR activation in CV-1 cells. However, it was not clear whether this effect of TNF-a was due to decreased expression of VDR.