Full Functional Knockout of Placental Growth Factor by Knockin with an Inactive Variant Able to Heterodimerize with VEGF-A

Placental growth factor (PlGF) is a proangiogenic member of the vascular endothelial growth factor (VEGF) family playing a central role in pathological angiogenesis. PlGF-DE is a PlGF variant unable to bind vascular endothelial growth factor receptor 1 (VEGFR-1) but still able to generate heterodimer with VEGF-A. We have generated PlGF-DE knockin mice that are vital and fertile and show unaltered expression of Plgf, Vegf-a, Vegfr-1, and Vegfr-2 compared with wild-type mice. Interestingly, these mutants showed additional and remarkable angiogenesis impairment in tumor growth, hindlimb ischemia, and choroidal neovascularization compared with both PlGF knockout and wild-type mice. These findings provided insights on VEGF-A/PlGF heterodimer function, which was able to rescue neovascularization and vascular leakage in PlGF-DE knockin mice. Collectively, these data show that PlGF-DE knockin mouse could be considered the full functional knockout of PlGF, suggesting a reassessment of the phenotypes of knockout mice for the genes whose products are able to generate heterodimeric proteins. Apicella et al. suggest a reconsideration of the phenotypes of knockout mice for molecular factors able to generate heterodimeric proteins. Knockin of Plgf, with a non-functional variant able to generate heterodimers with VEGF-A, determines additional pathological angiogenesis impairment compared with Plgf knockout, definitively proving the proangiogenic function of VEGF-A/PlGF heterodimers.