Endothelial GABBR2 Regulates Post-ischemic Angiogenesis by Inhibiting the Glycolysis Pathway

Abstract

Purpose: Angiogenesis post-ischemia plays an essential role in preventing ischemic damage to tissue by improving the blood recovery. Determining the regulatory mechanism of ischemic angiogenesis, therefore, could provide effective therapeutics for ischemic injury.Materials and Methods: The RNA sequencing (RNA-seq) database was used to predict the association of gamma-aminobutyric acid type B receptor subunit 2 (GABBR2) with endothelial-specific expression. The role of GABBR2 in angiogenesis was verified in vitro by downregulating GABBR2 in human umbilical vein endothelial cells (HUVECs) with lentiviral vectors. Besides, the in vivo effect of GABBR2 on the blood recovery of an ischemic hindlimb was demonstrated by establishing a hindlimb ischemia model in normal and GABBR2 adenoviral vector-infected mice. Then, the mobilization of endothelial progenitor cells (EPCs) in peripheral blood post-ischemia was determined by flow cytometry. Finally, the XF analyzer and Western blot were used to determine the effect of GABBR2 on endothelial metabolism.Results: The RNA-seq results indicated a strong association between GABBR2 and endothelial revascularization, and the upregulation of GABBR2 was detected in both hypoxia-treated HUVECs and ischemic mouse hindlimb. Hypoxia treatment for 6 h increased the proliferation, migration, and tube formation of HUVECs, which were inhibited by GABBR2 knockdown. Additionally, GABBR2 downregulation significantly decreased the blood flow recovery of mouse ischemic hindlimb. The expressions of the EPC markers CD34+ and CD133+ significantly decreased in the peripheral blood in hindlimb post-ischemia. Mechanically, glycolysis-dominated metabolism of HUVECs was compromised by GABBR2 knockdown. Evidences of the decreased expressions of HKII, PFKFB3, and PKM1 also supported the compromised glycolysis induced by GABBR2 downregulation.Conclusion: Our study demonstrated that GABBR2 regulated angiogenesis post-ischemia by inhibiting the glycolysis pathway.

Early-stage effect of HIBD on neuro-motor function and organic composition of neurovascular units in neonatal rats

“…In summary, the initial downregulation of CD31 post-modeling and its subsequent increase signifies the dynamic transformations within the vascular endothelial cells and their repair mechanisms. Furthermore, CD31 expression is closely associated with the restoration of cerebral blood flow and the promotion of angiogenesis, which emphasizes the significance of vascular endothelial repair mechanisms in the alleviation of tissue damage following ischemic events (Zhang et al, 2021).…”

Microevolutionary mechanism of high‐altitude adaptation in Tibetan chicken populations from an elevation gradient

“…We also identified some novel genes that may be highly related to high‐altitude adaptation with high selection. For example, we found that GABBR2 , which encodes a subclass of receptors to regulate the Ca 2+ concentration (Wang, Li, et al, 2015 ) and plays an essential role in preventing ischemic damage to tissue (Zhang et al, 2021 ), was highly selected. Here, we detected ZMIZ1 , which plays a crucial role in vasculogenesis and heart morphogenesis (Beliakoff et al, 2008 ) and may contain super‐enhancer SNPs that are associated with coronary artery disease (Gong et al, 2018 ).…”