Stimulatory G-Protein α Subunit Modulates Endothelial Cell Permeability Through Regulation of Plasmalemma Vesicle-Associated Protein

Lifan He; Hanlin Lu; Xuyang Ji; Jianying Chu; Xiaoteng Qin; Min Chen; Lee S Weinstein; Jiangang Gao; Jianmin Yang; Qunye Zhang; Cheng Zhang; Wencheng Zhang

doi:10.3389/fphar.2022.941064

Stimulatory G-Protein α Subunit Modulates Endothelial Cell Permeability Through Regulation of Plasmalemma Vesicle-Associated Protein

Front Pharmacol. 2022 Jun 3:13:941064. doi: 10.3389/fphar.2022.941064. eCollection 2022.

Authors

Lifan He¹, Hanlin Lu¹, Xuyang Ji^{1

2}, Jianying Chu³, Xiaoteng Qin¹, Min Chen⁴, Lee S Weinstein⁴, Jiangang Gao⁵, Jianmin Yang¹, Qunye Zhang¹, Cheng Zhang¹, Wencheng Zhang^{1

2}

Affiliations

¹ The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Department of Cardiology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
² Cardiovascular Disease Research Center of Shandong First Medical University, Central Hospital Affiliated to Shandong First Medical University, Jinan, China.
³ Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University, Jinan, China.
⁴ Metabolic Diseases Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States.
⁵ School of Life Science and Key Laboratory of the Ministry of Education for Experimental Teratology, Shandong University, Jinan, China.

Abstract

Endothelial cell leakage occurs in several diseases. Intracellular junctions and transcellular fashion are involved. The definite regulatory mechanism is complicated and not fully elucidated. The alpha subunit of the heterotrimeric G-stimulatory protein (Gsα) mediates receptor-stimulated production of cyclic adenosine monophosphate (cAMP). However, the role of Gsα in the endothelial barrier remains unclear. In this study, mice with knockout of endothelial-specific Gsα (Gsα^ECKO) were generated by crossbreeding Gsα^flox/flox mice with Cdh5-CreER^T2 transgenic mice, induced in adult mice by tamoxifen treatment. Gsα^ECKO mice displayed phenotypes of edema, anemia, hypoproteinemia and hyperlipoproteinemia, which indicates impaired microvascular permeability. Mechanistically, Gsα deficiency reduces the level of endothelial plasmalemma vesicle-associated protein (PLVAP). In addition, overexpression of Gsα increased phosphorylation of cAMP response element-binding protein (CREB) as well as the mRNA and protein levels of PLVAP. CREB could bind to the CRE site of PLVAP promoter and regulate its expression. Thus, Gsα might regulate endothelial permeability via cAMP/CREB-mediated PLVAP expression.

Keywords: CREB; Gsα; PLVAP; edema; endothelial permeability.