Adenovirus-mediated gene transfer of placental growth factor to perivascular tissue induces angiogenesis via upregulation of the expression of endogenous vascular endothelial growth factor-A

Placental growth factor (PIGF) is a member of the vascular endothelial growth factor (VEGF) family that binds specifically to VEGF receptor (VEGFR)-1. However, the mechanism of PIGF- and VEGFR-1-mediated angiogenesis has remained unclear and some in vitro studies suggest that VEGF-A/VEGFR-2 signaling may also play a role in PIGF-mediated angiogenesis. To clarify these issues we evaluated angiogenic responses in a well-characterized periadventitial angiogenesis model using adenovirus-mediated PIGF-2 (AdvPIGF-2) gene transfer. We also investigated the roles of VEGFR-1 and VEGFR-2 in PIGF-2-mediated angiogenesis. Using a periadventitial collar technique, AdvPIGF-2 (1 x 10(9) plaque-forming units/ml) was transferred to the adventitia of New Zealand White rabbits alone or together with adenoviruses encoding soluble VEGFR-1 (sVEGFR-1) or soluble VEGFR-2 (sVEGFR-2). Adenoviruses encoding LacZ were used as controls. All animals were killed 7 days after gene transfer. Increased neovessel formation, upregulation of endogenous VEGF-A expression, and a significant inflammatory response were seen in AdvPIGF-2-transduced arteries. The neovessels were large and well perfused. sVEGFR-1 and sVEGFR-2 suppressed the angiogenic response of PIGF-2 by 80 and 71.7%, respectively. We conclude that adenovirus-mediated PIGF-2 gene transfer to vascular tissue increases endogenous VEGF-A expression and produces significant angiogenesis. Both sVEGFR-1 and sVEGFR-2 can inhibit PIGF-2-mediated angiogenesis. PIGF-2 is a potentially useful candidate for the induction of therapeutic angiogenesis in vivo.