Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions

Vascular endothelial growth factor (VEGF) stimulates angiogenesis by activating VEGF receptor-2 (VEGFR-2). The role of its homolog, placental growth factor (PIGF), remains unknown. Both VEGF and PIGF bind to VEGF receptor-1 (VEGFR-1), but it is unknown whether VECFR-1, which exists as a soluble or a membrane-bound type, is an inert decoy or a signaling receptor for PIGF during angiogenesis. Here, we report that embryonic angiogenesis in mice was not affected by deficiency of PIGF (Pgf(-/-)). VEGF-B, another ligand of VEGFR-1, did not rescue development in Pgf(-/-) mice. However, loss of PIGF impaired angiogenesis, plasma extravasation and collateral growth during ischemia, inflammation, wound healing and cancer. Transplantation of wild-type bone marrow rescued the impaired angiogenesis and collateral growth in Pgf(-/-) mice, indicating that PIGF might have contributed to vessel growth in the adult by mobilizing bone-marrow-derived cells. The synergism between PIGF and VEGF was specific, as PIGF deficiency impaired the response to VEGF, but not to bFGF or histamine. VECFR-1 was activated by PIGF, given that anti-VEGFR-1 antibodies and a Src-kinase inhibitor blocked the endothelial response to PIGF or VEGF/PIGF. By upregulating PIGF and the signaling subtype of VEGFR-1, endothelial cells amplify their responsiveness to VEGF during the 'angiogenic switch' in many pathological disorders.