Perlecan, a secreted heparan sulfate proteoglycan, is a major component of the Vascular basement membrane and participates in angiogenesis Here, we used small interference RNA-mediated knockdown perlecan expression to investigate the regulatory function of perlecan in the growth of human endothelial cells. Basic fibroblast growth factor (bFGF)-induced ERK phosphorylation and cyclin D1 expression were unchanged by perlecan deficiency in endothelial cells; however, perlecan inhibited the Rb protein phosphorylation and DNA synthesis induced by bFGF By contrast to localization of the cyclin-dependent kinase inhibitor p27 in control endothelial cells, p27 was localized in the nucleus and its expression increased in perlecan-deficient cells, which suggests that p27 mediates inhibition of Rb phosphorylation In addition to the well-characterized function of perlecan as a co-receptor for heparin-binding growth factors such as bFGF. our results suggest that perlecan plays an indispensible role in endothelial cell proliferation and acts through a mechanism that involves localization of p27 (C) 2010 Elsevier Inc. All rights reserved