Disruption of profilin1 function suppresses developmental and pathological retinal neovascularization

Gau D, Vignaud L, Allen A, Guo Z, Sahel J, Boone D, Koes D, Guillonneau X, Roy P. Disruption of profilin1 function suppresses developmental and pathological retinal neovascularization. Journal of Biological Chemistry 2020 Jul 10;295(28):9618-9629.

doi: 10.1074/jbc.RA120.012613. PMID 32444495

Angiogenesis-mediated neovascularization in the eye is usually associated with visual complications. Pathological angiogenesis is particularly prominent in the retina in the settings of proliferativediabeticretinopathy,inwhichitcanleadtopermanent loss of vision. In this study, by bioinformatics analyses, we provide evidence for elevated expression of actin-binding protein PFN1 (profilin1) in the retinal vascular endothelial cells (VECs) of individuals with proliferative diabetic retinopathy, findings further supported by gene expression analyses for PFN1inexperimentallyinducedabnormalretinalneovascularization in an oxygen-induced retinopathy murine model. We observedthatinaconditionalknockoutmousemodel,postnatal deletion of the Pfn1 gene in VECs leads to defects in tip cell activity (marked by impaired filopodial protrusions) and reduced vascular sprouting, resulting in hypovascularization during developmental angiogenesis in the retina. Consistent with these findings, an investigative small molecule compound targeting thePFN1–actininteractionreducedrandommotility,proliferation, and cord morphogenesis of retinal VECs 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.Theproofofconceptofsusceptibilityofabnormalangiogenesis 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.

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2020
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Gau D, Vignaud L, Allen A, Guo Z, Sahel J, Boone D, Koes D, Guillonneau X, Roy P
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