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

Abstract

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

Endothelial progenitor cells for cancer gene therapy

“…Placental growth factorwhich signals primarily through VEGFR1-also contributes to vessel growth in tumors, possibly by recruiting bone marrow-derived cells. 30 VEGF and placental growth factor are released by many tumors. Inhibition of VEGF 31,32 inhibits tumor growth.…”

“…The simultaneous inhibition of both receptors impairs mobilization of bone marrow-derived cells to the tumor vasculature and retards tumor growth. 18,30,33 Recent data show that stromal-derived factor 1 (SDF-1/CXCL12) contributes to the recruitment of EPCs to tumors and their retention in the tumor vessels. 27,34,35 …”

PIGF Knockout Delays Brain Vessel Growth and Maturation upon Systemic Hypoxic Challenge

“…Placental growth factor wild-type and knockout mice (generated by Carmeliet et al (2001); Vesalius Research Center, Leuven, Belgium) were bred at the NRCC (National Research Council of Canada) Institute for Biological Sciences Animal Facility (Ottawa, ON, Canada). Experiments were approved by the NRCC animal care committee in accordance with the Canadian Council on Animal Care guidelines.…”

Vascular endothelial growth factor-B: Impact on physiology and pathology

“…93 The other members, VEGF-A 94 and PlGF 95 also showed protective ability. Howbeit, the risk of adverse effects, consisting of bleeding, leakage, hypotension, malignancy, had limited clinically systemic administration of VEGF-A for the revascularization of ischemic tissues; 96 and the Ad-PlGF induced myocardial angiogenesis and cardiac hypertrophy was abolished by the nitric oxide synthase inhibitor L-arginine Methyl Ester (L-NAME).…”

“…To explain these different effects, Ad-VEGF-B 186 and Ad-PlGF might signal through different receptor binding sites and/or structural variants, or alternatively, acted by recruiting distinct co-receptors to the signaling complex, 13 thereby inducing various downstream events, 77 which was verified since VEGF-B did not rescue development in PlGF deficiency mice. 95 In comparison, the VEGF-B has marked superiority over its family members. First, VEGF-B showed high selectivity to stimulate angiogenesis, especially in the ischemic myocardium, 18 being expected to stimulate angiogenic without causing adverse effects.…”