With about two million procedures performed worldwide every year (www.ptca.org), percutaneous transluminal coronary angioplasty (PTCA) remains the preferred method of coronary revascularisation following heart attack. The development of drug-eluting stents has greatly improved the outcome following vascular intervention but restenosis remains an important reason for the failure of revascularisation. The abnormal accumulation of neointimal vascular smooth muscle cells (VSMC) resulting from both media-to-intima migration and proliferation is the major underlying cause of restenosis. These processes, together with deposition of extracellular matrix, lead to neointimal hyperplasia, causing luminal narrowing, limiting the beneficial effects of the intervention. Neuropilin 1 (NRP1) and 2 (NRP2) are versatile membrane co-receptors playing crucial roles in the developing cardiovascular and neuronal systems, but also in adult physiological and pathophysiological settings such as the primary immune response and cancer 1. NRP1 and 2 share an overall amino acid homology of 44% and a similar domain structure. NRP1 null mice die in utero between E12 and E13.5 with a spectrum of cardiovascular and neuronal defects. NRP2-deficient mice survive to adulthood with some abnormality in the fasciculation of certain cranial nerves and fewer and smaller lymphatic vessels, but no other obvious vascular defects 2,3. Neuropilins (NRPs) complex with VEGF receptors in the endothelium where they convey VEGF signaling 2 and therefore NRPs have been shown to be crucially important for endothelial cell migration and angiogenesis in several in vitro and in vivo models.Moreover, NRPs are also able to mediate cellular functions via non-canonical ligands involving signaling and the formation of complexes with other growth factor receptors, including PDGF/PDGFRs and transforming growth factor β (TGFβ) and its receptors 4. Neuropilins are highly expressed in VSMC, mesenchymal stem cells (MSC) and hepatic stellate cells where they have been shown to play a role in cell migration in response to platelet-derived growth factor (PDGF) by associating with PDGF receptors α and β (PDGFRα and PDGFRβ) and regulating their phosphorylation state and downstream chemotactic signaling 5. So far, the role of NRPs in VSMC migration in vivo has not been explored. Since PDGF signaling is a key regulator of VSMC migration and proliferation following endovascular injury, we examined whether NRPs play a role in the neointimal remodelling induced by balloon angioplasty in the rat carotid artery, a well-characterised model of arterial remodeling following endothelial denudation.We found that endogenous NRP1 and NRP2 were up-regulated both at mRNA and protein levels following arterial injury. The down-regulation of NRP1 and NRP2 expression via adventitial adenovirus delivery using shRNA constructs resulted in a clear reduction of neointimal hyperplasia following arterial injury, we then over-expressed wild-type (WT) NRP1 and a NRP1 mutant lacking the cytoplasmic domain (ΔC) and observed a decreased neointimal response with the NRP1 ΔC infection, whereas the NRP1 WT construct had no apparent effect. Bromodeoxyuridine (BrdU) staining revealed that in vivo proliferation was reduced in arteries transduced with the adenoviral shNRP2 construct only. In vitro studies carried on rat aortic smooth muscle cells (RAoSMC) supported this finding and shown limited proliferation ability for the cells in which NRP2 was knocked-down, whereas cell infected with the other adenoviral constructs (NRP1 WT, NRP1 ΔC, shNRP1) displayed no impaired proliferation in response to PDGF-BB. We used the transwell assay to assess RAoSMC chemotaxis and found that cells infected with NRP1 ΔC, shNRP1 and shNRP2 all displayed a reduced migration towards the PDGF-BB gradient, and this was in accordance with previous results in Human coronary artery smooth muscle cells (HCASMC) 5. Moreover, NRP1 and NRP2 are able to modulate PDGFR phosphorylation, which could critically affect SMC function and ultimately the extent of the neointima. Therefore, targeting NRPs expression in human VSMCs may represent an attractive approach for the treatment of proliferative vascular diseases.