Endothelial Nucleoporin93 (Nup93) Maintains Vascular Function via Sun1-Dependent Regulation of RhoA-eNOS Signaling

Area of Science:

• Vascular Biology
• Cellular Biology
• Molecular Biology

Background:

• Endothelial cells (ECs) maintain vascular health by producing nitric oxide (NO) via endothelial nitric oxide synthase (eNOS).
• The RhoA/ROCK pathway and aging-related nuclear pore complex (NPC) dysfunction can impair NO production and contribute to vasoconstriction.
• Sun1, a component of the LINC complex, regulates RhoA/ROCK activity, linking nuclear structure to cellular signaling.

Purpose of the Study:

• To investigate the role of endothelial Nup93 in regulating eNOS-NO signaling and vascular function.
• To elucidate the mechanism by which Nup93 influences RhoA/ROCK activity and Sun1 levels.
• To determine if Nup93 is a novel regulator of endothelial and vascular biology.

Main Methods:

• Targeted deletion of Nup93 in adult mouse endothelium.
• In vitro knockdown of Nup93 in primary human ECs.
• Assessment of eNOS expression, NO production, Sun1 levels, and RhoA activity.
• Rescue experiments restoring Sun1 levels in Nup93-deficient ECs.

Main Results:

• Endothelial Nup93 loss significantly reduced eNOS expression and NO bioavailability in mice and human ECs.
• Nup93 deficiency led to decreased endothelial Sun1 levels and increased RhoA activity.
• Restoring Sun1 levels in Nup93-deficient ECs normalized RhoA activity, eNOS expression, and NO production.

Conclusions:

• Endothelial Nup93 is a novel regulator of eNOS-NO signaling and vascular reactivity.
• Nup93 stabilizes Sun1, thereby modulating RhoA activity and maintaining NO production.
• Nuclear envelope components, including Nup93, play a critical role in endothelial and vascular homeostasis.