Motility of vascular smooth muscle cells (SMCs) is an essential step for both normal and pathologic angiogenesis. We report here that breast tumor cells, such as MCF‐7 and MDA‐MB‐231, can modulate this SMC migration. We present evidence that the tumor cell‐derived platelet‐derived growth factor (PDGF) is the key regulator of vascular SMCs motility induced by breast cancer cells. PDGF significantly upregulates neuropilin‐1 (NRP‐1) mRNA expression and protein production in aortic smooth muscle cells (AOSMCs) and depletion of NRP‐1 production by AOSMCs with specific short hairpin RNA (shRNA) prevents the PDGF‐dependent migration of vascular SMCs. Moreover, we demonstrate that PDGF physically interacts with NRP‐1. We propose that tumor‐derived PDGF and NRP‐1 of AOSMCs function as a relay system that promotes motility of vascular SMCs. © 2006 Wiley‐Liss, Inc.