FLRT2 prevents endothelial cell senescence and vascular aging by regulating the ITGB4/mTORC2/p53 signaling pathway

The roles of fibronectin leucine-rich transmembrane protein 2 (FLRT2) in physiological and pathological processes are not well known. Here, we identify a potentially novel function of FLRT2 in preventing endothelial cell senescence and vascular aging. We found that FLRT2 expression was lower in cult...

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Published in:JCI insight Vol. 9; no. 7
Main Authors: Hwang, Hyun Jung, Kang, Donghee, Kim, Jae-Ryong, Choi, Joon Hyuk, Ryu, Ji-Kan, Herman, Allison B., Ko, Young-Gyu, Park, Heon Joo, Gorospe, Myriam, Lee, Jae-Seon
Format: Journal Article
Language:English
Published: United States American Society for Clinical Investigation 08.04.2024
American Society for Clinical investigation
Subjects:
Aging
AKT protein
Animals
Antibodies
Cell biology
Cell cycle
Endothelial cells
Endothelial Cells - metabolism
Fibronectin
Genotype & phenotype
Humans
Integrin beta4 - genetics
Integrin beta4 - metabolism
Kinases
Mechanistic Target of Rapamycin Complex 2 - metabolism
Membrane Glycoproteins - metabolism
Mice
Morphology
p53 Protein
Phenotypes
Phosphorylation
Proteins
Rats
Senescence
Signal Transduction
TOR protein
Tumor Suppressor Protein p53 - genetics
Tumor Suppressor Protein p53 - metabolism
Vascular biology
Cell biology
Vascular biology
Cellular senescence
ISSN:2379-3708, 2379-3708
Online Access:Get full text
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Summary:The roles of fibronectin leucine-rich transmembrane protein 2 (FLRT2) in physiological and pathological processes are not well known. Here, we identify a potentially 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 mediated endothelial cell senescence via the mTOR complex 2, AKT, and p53 signaling pathway in human endothelial cells. We uncovered that FLRT2 directly associated with integrin subunit beta 4 (ITGB4) and thereby promoted ITGB4 phosphorylation, while inhibition of ITGB4 substantially 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. Therefore, we propose that FLRT2 could be targeted therapeutically to prevent senescence-associated vascular aging.
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ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.172678