TNF receptors regulate vascular homeostasis in zebrafish through a caspase-8, caspase-2 and P53 apoptotic program...

Area of Science:

• Vascular Biology
• Cell Signaling
• Apoptosis

Background:

• Tumor necrosis factor receptor (TNFR) signaling is critical for vascular integrity and homeostasis.
• The specific roles of individual TNFRs and their signaling pathways in endothelial cells remain largely unknown.

Purpose of the Study:

• To elucidate the distinct contributions of TNFRSF1A and TNFRSF1B to endothelial cell integrity.
• To identify the signaling pathways governing TNFR-mediated endothelial cell apoptosis and survival.

Main Methods:

• Gene knockdown of TNFRSF1B in zebrafish embryos.
• Analysis of apoptotic pathways involving caspases and p53.
• Investigating the roles of TNFRSF1A and NF-κB signaling.

Main Results:

• TNFRSF1B knockdown induces caspase-8, caspase-2, and p53-dependent endothelial cell apoptosis, bypassing caspase-3.
• Simultaneous depletion of TNFRSF1A or NF-κB activation rescues endothelial cell apoptosis.
• TNFRSF1A signals apoptosis via caspase-8, whereas TNFRSF1B signals survival via NF-κB in endothelial cells.
• TNFα induces human endothelial cell apoptosis through TNFRSF1A, activating caspase-2 and p53.

Conclusions:

• A delicate balance between TNFRSF1A and TNFRSF1B signaling is essential for maintaining endothelial cell integrity.
• An evolutionarily conserved apoptotic pathway in vascular homeostasis has been identified.
• This pathway presents potential therapeutic targets for managing angiogenesis in inflammation and cancer.