Efficient fine-tuning of endothelial gene expression by a single Tyrosine to Phenylalanine point mutation in theVE-cadheringene

Abstract

We aimed at understanding whether the site Y685 of VE-cadherin triggers epigenetic programming in vivo. Using our knock-in mice carrying the Y685F VE-cadherin mutation, RNA sequencing from lung ECs identified 884 differentially expressed genes (DEGs) involved in cell-cell adhesion, vascular development, and angiogenesis. Analysis of the VEGF/VEGFR2 signaling pathway shows a significant decrease in the expression of pY1173VEGFR2 whereas VEGF remains constant, this was consistent with impaired migration, proliferation and protrusive properties of ECs in vitro. Co-immunoprecipitation experiments showed that c-Src and Y685F VE-cadherin association which was enhanced in KI compared to WT, resulting in increased in Y685F-VE-cadherin phosphorylation at site Y731. As a consequence, its partner b-catenin translocates to the nucleus. Using CHIPS assay we demonstrate that FOXF1 binds to the s1pr1 promoter, leading to increased expression of the S1PR1, a process associated with increased vessel wall thickness and reduced fibrosis in the lung vasculature in vivo. Overall, our findings provide a novel transcriptomic profile triggered by Y685F-VE-cadherin ECs for potential insights into therapeutic targets to envisage normalisation of the tumor vasculature.