CREB Coactivator CRTC2 Plays a Crucial Role in Endothelial Function

The cAMP pathway is known to stabilize endothelial barrier function and maintain vascular physiology. The family of cAMP-response element binding (CREB)-regulated transcription coactivators (CRTC)1-3 activate transcription by targeting the basic leucine zipper domain of CREB. CRTC2 is a master regulator of glucose metabolism in liver and adipose tissue. However, the role of CRTC2 in endothelium remains unknown. The aim of this study was to evaluate the effect of CRTC2 on endothelial function. We focused the effect of CRTC2 in endothelial cells and its relationship with p190RhoGAP-A. We examined the effect of CRTC2 on endothelial function using a mouse aorta ring assay ex vivo and with photothrombotic stroke in endothelial cell-specific CRTC2-knock-out male mice in vivo. CRTC2 was highly expressed in endothelial cells and related to angiogenesis. Among CRTC1-3, only CRTC2 was activated under ischemic conditions at endothelial cells, and CRTC2 maintained endothelial barrier function through p190RhoGAP-A expression. Ser(171) was a pivotal regulatory site for CRTC2 intracellular localization, and Ser(307) functioned as a crucial phosphorylation site. Endothelial cell-specific CRTC2-knock-out mice showed reduced angiogenesis ex vivo, exacerbated stroke via endothelial dysfunction, and impaired neurologic recovery via reduced vascular beds in vivo. These findings suggest that CRTC2 plays a crucial protective role in vascular integrity of the endothelium via p190RhoGAP-A under ischemic conditions.