FLRT2 plays a critical role in endothelial cell senescence and vascular aging

Abstract

Abstract The roles of fibronectin leucine-rich transmembrane protein 2 (FLRT2) in physiological and pathological processes are poorly known. Here, we identify a novel function of FLRT2 in preventing endothelial cell senescence and vascular aging. We found that FLRT2 expression was lower in cultured senescent endothelial cells as well as in aged rat and human vascular tissues. FLRT2 silencing in human endothelial cells induced senescence through mTORC2, but not mTORC1, AKT, and p53. We uncovered that FLRT2 directly associated with ITGB4 and thereby promoted ITGB4 phosphorylation, while inhibition of ITGB4 significantly mitigated the induction of senescence triggered by FLRT2 depletion. Importantly, FLRT2 silencing in mice promoted vascular aging and overexpression of FLRT2 rescued a premature vascular aging phenotype. We propose that FLRT2 could be targeted therapeutically to prevent senescence-associated vascular aging. Subject terms: FLRT2, ITGB4, mTORC2, endothelial cell senescence, vascular aging