Rap1 small GTPase is essential for maintaining pulmonary endothelial barrier function in mice

Area of Science:

• Molecular Biology
• Cell Biology
• Physiology

Background:

• Vascular permeability is regulated by VE-cadherin at endothelial cell junctions.
• Impaired junctions cause hyperpermeability, linked to disease progression.
• Pulmonary inflammation and infection often lead to lung vascular leakage.

Purpose of the Study:

• To investigate the role of the small GTPase Rap1 in maintaining pulmonary endothelial barrier function.
• To understand Rap1's mechanism in regulating VE-cadherin-mediated cell adhesions.
• To assess Rap1's protective effect against inflammation-induced vascular leakage in the lungs.

Main Methods:

• Generated endothelial cell-specific Rap1a/Rap1b double knockout mice.
• Utilized en face and 3D-immunofluorescence analyses of mouse lungs and pulmonary arteries.
• Administered lipopolysaccharide (LPS) and an Epac activator (007) to assess vascular permeability.

Main Results:

• Rap1 knockout mice developed severe pulmonary edema and cardiac vascular leakage.
• Rap1 stabilizes VE-cadherin junctions via actin cytoskeleton reorganization, inhibiting Rho-ROCK-NM-II and promoting junctional NM-II.
• Rap1 deficiency increased susceptibility to LPS-induced leakage; Rap1 activation by 007 attenuated this leakage.

Conclusions:

• Rap1 is essential for maintaining pulmonary endothelial barrier integrity under physiological conditions.
• Rap1 protects against inflammation-induced pulmonary vascular leakage by reinforcing endothelial cell-cell junctions.
• Targeting Rap1 signaling may offer therapeutic strategies for inflammatory lung diseases.