Disruption of profilin1 function suppresses developmental and pathological retinal neovascularization.

: Angiogenesis-mediated neovascularization in eye is usually associated with visual complications. Pathological angiogenesis is particularly prominent in the retina in the settings of proliferative diabetic retinopathy (PDR) in which it can lead to permanent loss of vision. In this study, by bioinformatics analyses, we provide evidence for elevated expression of actin-binding protein profilin1 (PFN1) in the retinal vascular endothelial cells (VEC) of individuals with PDR, findings further supported by gene expression analyses for PFN1 in experimentally induced abnormal retinal neovascularization in oxygen-induced retinopathy (OIR) murine model. We observed that in a conditional knockout mouse model, post-natal deletion of the Pfn1 gene in VEC leads to defects in tip cell activity (marked by impaired filopodial protrusions) and reduced vascular sprouting resulting in hypo-vascularization during developmental angiogenesis in the retina. Consistent with these findings, an investigative small molecule compound targeting the PFN1-actin interaction reduced random motility, proliferation and cord morphogenesis of retinal VEC in vitro and experimentally induced abnormal retinal neovascularization in vivo. In summary, these findings provide the first direct in vivo evidence that PFN1 is required for formation of actin-based protrusive structures and developmental angiogenesis in the retina. The proof-of-concept of susceptibility of abnormal angiogenesis to small molecule intervention of PFN1-actin interaction reported here lays a conceptual foundation for targeting PFN1 as a possible strategy in angiogenesis-dependent retinal diseases.