Endothelial RAP1A attenuates sinusoidal capillarisation and liver fibrosis by inhibiting RAF1-mediated Notch...

Area of Science:

• Hepatology
• Endothelial Biology
• Molecular Mechanisms of Fibrosis

Background:

• Capillarisation of liver sinusoidal endothelial cells (LSECs) is an early event in liver fibrogenesis, promoting hepatic stellate cell activation.
• Ras-associated protein 1A (RAP1A) has been implicated in liver fibrosis, but its specific role in LSEC capillarisation is unknown.

Purpose of the Study:

• To investigate the role of the endothelial GTPase RAP1A in LSEC capillarisation and the development of liver fibrosis.
• To elucidate the molecular mechanisms by which RAP1A influences these processes.

Main Methods:

• Established liver fibrosis models using HFHCD, CDAHFD, CCl4, or DDC treatments in mice.
• Generated endothelial-specific Rap1a knockout (Rap1aΔEC) mice.
• Utilized a RAP1 activator (8-pCPT-2'-O-Me-cAMP) for therapeutic intervention.
• Assessed LSEC capillarisation, liver fibrosis, and inflammation.

Main Results:

• RAP1A expression was downregulated in LSECs during fibrosis and in vitro capillarisation.
• Endothelial Rap1a deficiency accelerated LSEC capillarisation and liver fibrosis, exacerbating CCl4/DDC-induced injury.
• RAP1A loss promoted RAF1 degradation, enhancing Notch signaling activation.
• Pharmacological RAP1A activation reduced LSEC capillarisation and liver fibrosis.

Conclusions:

• Endothelial Rap1a deficiency aggravates LSEC capillarisation and liver fibrosis via Notch signaling activation through RAF1 degradation.
• Rap1a is crucial for maintaining LSEC homeostasis.
• Rap1a represents a promising therapeutic target for liver fibrosis.