Rictor, an mTORC2 Protein, Regulates Murine Lymphatic Valve Formation Through the AKT-FOXO1 Signaling

Area of Science:

• Vascular biology
• Cell signaling
• Mechanobiology

Background:

• Lymphatic valves are vital for preventing lymph backflow and their proper formation is crucial for preventing congenital lymphedema.
• Lymphatic valve development is regulated by the PI3K/AKT pathway in response to shear stress.
• The role of mammalian target of rapamycin complex 2 (mTORC2) in lymphatic valve formation was previously unknown.

Purpose of the Study:

• To investigate the role of RICTOR, a key component of mTORC2, in lymphatic valve development.
• To elucidate the signaling mechanisms by which RICTOR influences lymphatic valve formation.

Main Methods:

• Utilized in vivo and in vitro techniques to study lymphatic endothelium.
• Performed embryonic and postnatal lymphatic deletion of Rictor in mice.
• Conducted RICTOR knockdown in human dermal lymphatic endothelial cells.
• Analyzed AKT activity, gene expression, and FOXO1 nuclear localization.

Main Results:

• Lymphatic deletion of Rictor significantly reduced lymphatic valves and impaired collecting lymphatic vessel maturation.
• RICTOR knockdown decreased AKT activation and valve-forming gene expression, abolishing responses to shear stress.
• Rictor deficiency led to increased nuclear FOXO1 activity, a repressor of valve formation.
• Deletion of Foxo1 in Rictor-deficient mice rescued lymphatic valve formation.

Conclusions:

• Identifies a novel role for RICTOR in the mechanotransduction pathway regulating lymphatic valve formation.
• RICTOR activates AKT, which in turn inhibits nuclear FOXO1 accumulation, promoting lymphatic valve development and maintenance.