The SWELL1-LRRC8 complex regulates endothelial AKT-eNOS signaling and vascular function

Area of Science:

• Endothelial biology
• Vascular physiology
• Molecular mechanisms of mechanotransduction

Background:

• The endothelium regulates vascular tone, blood pressure, and flow via chemical and mechanical signals.
• Endothelial volume-regulated anion channels (VRACs) are implicated in mechanosensation and vascular regulation.
• LRRC8A (SWELL1) is a key component of VRACs, but its role in endothelial mechanotransduction is not fully understood.

Purpose of the Study:

• To investigate the role of LRRC8A in endothelial mechanosensation and vascular function.
• To determine LRRC8A's involvement in AKT-eNOS signaling pathways under various flow conditions.
• To assess the impact of endothelial LRRC8A deficiency on vascular health, particularly in the context of type 2 diabetes.

Main Methods:

• Utilized human umbilical vein endothelial cells (HUVECs) to study LRRC8A function.
• Employed genetic knockout models (endothelium-restricted Lrrc8a KO mice).
• Assessed AKT-eNOS signaling, endothelial cell alignment, and vascular responses to stimuli like stretch and shear flow.

Main Results:

• LRRC8A is required for VRAC function in HUVECs.
• Endothelial LRRC8A regulates AKT-eNOS signaling under basal, stretch, and shear-flow conditions.
• LRRC8A is essential for endothelial cell alignment to laminar shear flow.
• Endothelium-restricted Lrrc8a KO mice developed hypertension and impaired retinal blood flow, particularly in a type 2 diabetes model.

Conclusions:

• LRRC8A is a critical regulator of endothelial AKT-eNOS signaling and vascular function.
• LRRC8A plays a vital role in maintaining vascular integrity and blood flow regulation.
• Targeting LRRC8A may offer therapeutic potential for vascular complications associated with type 2 diabetes.