CREB Coactivator CRTC2 Plays a Crucial Role in Endothelial Function

Area of Science:

• Vascular Biology
• Molecular Mechanisms of Endothelial Function
• Transcriptional Regulation

Background:

• The cAMP pathway is vital for endothelial barrier function and vascular health.
• CRTC2 (CREB-regulated transcription coactivator 2) is a known regulator of glucose metabolism but its role in endothelium was unexplored.
• CRTC1-3 are transcription coactivators targeting CREB.

Purpose of the Study:

• To investigate the role of CRTC2 in endothelial cells and its impact on endothelial function.
• To elucidate the relationship between CRTC2 and p190RhoGAP-A in the endothelium.
• To evaluate the effect of CRTC2 on vascular integrity and recovery under ischemic conditions.

Main Methods:

• Ex vivo mouse aorta ring assay to assess endothelial function.
• In vivo studies using endothelial cell-specific CRTC2-knock-out male mice subjected to photothrombotic stroke.
• Analysis of CRTC2 expression, localization, and phosphorylation sites (Ser171, Ser307).

Main Results:

• CRTC2 is highly expressed in endothelial cells and associated with angiogenesis.
• Only CRTC2, among CRTC1-3, was activated in endothelial cells under ischemic conditions.
• CRTC2 maintained endothelial barrier function through p190RhoGAP-A expression; Ser307 is a crucial phosphorylation site.
• CRTC2-knock-out mice exhibited reduced angiogenesis, exacerbated stroke, and impaired neurological recovery due to reduced vascular beds.

Conclusions:

• CRTC2 plays a critical protective role in maintaining endothelial vascular integrity via p190RhoGAP-A under ischemic stress.
• CRTC2 activation in endothelial cells is crucial for angiogenesis and recovery post-stroke.
• CRTC2 represents a potential therapeutic target for mitigating blood-brain barrier damage and enhancing recovery after ischemic events.