Aging-regulated PNUTS maintains endothelial barrier function via SEMA3B suppression.

Area of Science:

• Endothelial cell biology
• Aging research
• Vascular homeostasis

Background:

• Endothelial senescence contributes to age-related cardiovascular disease.
• Phosphatase 1 Nuclear Targeting Subunit (PNUTS) is implicated in cardiomyocyte aging.
• The role of PNUTS in endothelial cell aging requires investigation.

Purpose of the Study:

• To elucidate the function of PNUTS in endothelial cell aging and homeostasis.
• To identify downstream pathways regulated by PNUTS in endothelial cells.
• To explore potential therapeutic targets for age-related endothelial dysfunction.

Main Methods:

• PNUTS silencing in human umbilical vein endothelial cells (HUVECs).
• Generation and analysis of endothelial-specific inducible PNUTS-deficient mice (PNUTS^EC-KO).
• Transcriptomic analysis (RNA-seq) of silenced HUVECs and mouse lung tissue.
• Assessment of endothelial senescence, angiogenesis, barrier function, and organ integrity.

Main Results:

• PNUTS expression is reduced in senescent endothelial cells.
• PNUTS deficiency in vitro and in vivo recapitulates hallmarks of endothelial aging, including senescence and barrier dysfunction.
• PNUTS deletion in mice leads to multiorgan failure and vascular leakage.
• The PNUTS-PP1 complex regulates semaphorin 3B (SEMA3B) expression.
• SEMA3B knockdown rescues endothelial barrier function following PNUTS loss.

Conclusions:

• PNUTS plays a critical role in maintaining endothelial cell homeostasis and preventing premature aging.
• The PNUTS-SEMA3B axis is a key regulator of endothelial barrier integrity.
• Targeting the PNUTS-SEMA3B pathway offers a potential strategy to combat age-related endothelial dysfunction and vascular diseases.