CREB Coactivator CRTC2 Plays a Crucial Role in Endothelial Function

Abstract

The cAMP pathway is known to stabilize endothelial barrier function and maintain vascular physiology. The family of cAMPresponse 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.

MiRNA-132/212 regulates tight junction stabilization in blood–brain barrier after stroke

“…MiR-132/212 is a well-studied miRNA cluster in CNS disorders such as neurogenerative diseases [ 26 ] and intracerebral hemorrhage [ 27 ]. CREB-regulated transcription coactivator (CRTC) includes CRTC1, CRTC2, and CRTC3, among which CRTC2 has been demonstrated to dictate the vascular endothelial function [ 28 ], and CRTC1 is a specifically expressed protein in neuron. CRTC1 has been suggested to act as a critical role in several neurodegenerative diseases, such as Alzheimer’s disease [ 29 – 31 ], and Huntington’s disease [ 32 , 33 ].…”

The tight junction protein occludin modulates blood–brain barrier integrity and neurological function after ischemic stroke in mice

“…Photochemically induced thrombosis ( PIT) leading to cerebral infarction was developed according to the method we had previously reported 49 . Adult male and female mice aged 8–12 weeks were anesthetized with isoflurane in an induction chamber with 100% oxygen.…”

Biological functions of CRTC2 and its role in metabolism-related diseases

“…Experiments have shown that CRTC2 is highly expressed in endothelial cells and is related to the formation of blood vessels. Under the condition of ischemia, CRTC2 can protect the integrity of endothelial cells through P190RhoGAP‐a, and the cAMP pathway can also stabilize the endothelial barrier function, to maintain the physiological function of blood vessels (Kanki et al 2020). The concept that vascular smooth muscle cells (VSMCs) exist in a transitional phase between atherosclerotic smooth muscle and foam cells in humans was first proposed with the help of electron microscopy in 1961(Geer et al 1961).…”

“…With the aggravation of heart failure, the myocardial blood supply gradually decreases. When the myocardium is in a state of ischemia, P190RhoGAP‐a is activated, which affects the angiogenesis, reduces the endothelial barrier function, aggravates heart failure, and further decreases the blood supply, forming a vicious cycle (Kanki et al 2020). Therefore, CRTC2 can affect the structure and active site of CRTC2 in heart failure through SREBP and its effect on endothelial cells.…”