Yong-Ping Bai1, Songhua Xiao, Yong-Bo Tang, Zhi Tan, Hailin Tang, Zhi Ren, Haitao Zeng, Zhen Yang. 1. aDepartment of Geriatric Medicine, Xiangya Hospital, Central South University, Changsha, Hunan bDepartment of Neurology, Sun Yat-Sen Memorial Hospital cDepartment of Pharmacology, Zhongshan School of Medicine dDepartment of Physiology, Zhongshan School of Medicine, Sun Yat-Sen University eSun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine fCenter for Reproductive Medicine, The Sixth Affiliated Hospital gDepartment of Hypertension & Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, People's Republic of China.
Abstract
OBJECTIVES: Guanosine triphosphate cyclohydrolase/tetrahydrobiopterin (GTPCH)/(BH4) pathway has been proved to regulate the function of endothelial progenitor cells (EPCs) in deoxycorticosterone acetate-salt hypertensive mice, indicating that GTPCH/BH4 pathway may be an important repair target for hypertension-related endothelial injury. Shear stress is an important nonpharmacologic strategy to modulate the function of EPCs. Here, we investigated the effects of laminar shear stress on the GTPCH/BH4 pathway and endothelial repair capacity of circulating EPCs in hypertension. METHOD: Laminar shear stress was loaded on the human EPCs from hypertensive patients and normotensive patients. The in-vitro function, in-vivo reendothelialization capacity and GTPCH/BH4 pathway of human EPCs were evaluated. RESULTS: Both in-vitro function and reendothelialization capacity of EPCs were lower in hypertensive patients than that in normotensive patients. The GTPCH/BH4 pathway of EPCs was downregulated in hypertensive patients. Shear stress increased in-vitro function and reendothelialization capacity of EPCs from hypertensive patients and normotensive patients. Furthermore, shear stress upregulated the expression of GTPCH I and levels of BH4, nitric oxide, and cGMP of EPCs, and reduced thrombospondin-1 expression. With treatment of GTPCH knockdown or nitroarginine methyl ester inhibition, shear stress-induced increased levels of BH4, nitric oxide and cGMP of EPCs was suppressed. When GTPCH/BH4 pathway of EPCs was blocked, the effects of shear stress on in-vitro function and reendothelialization capacity of EPCs were inhibited. CONCLUSION: The study demonstrates for the first time that shear stress-induced upregulation of the GTPCH/BH4 pathway ameliorates hypertension-related decline in endothelial repair capacity of EPCs. These findings provide novel nonpharmacologic therapeutic approach for hypertension-related endothelial repair.
OBJECTIVES:Guanosine triphosphate cyclohydrolase/tetrahydrobiopterin (GTPCH)/(BH4) pathway has been proved to regulate the function of endothelial progenitor cells (EPCs) in deoxycorticosterone acetate-salthypertensivemice, indicating that GTPCH/BH4 pathway may be an important repair target for hypertension-related endothelial injury. Shear stress is an important nonpharmacologic strategy to modulate the function of EPCs. Here, we investigated the effects of laminar shear stress on the GTPCH/BH4 pathway and endothelial repair capacity of circulating EPCs in hypertension. METHOD: Laminar shear stress was loaded on the human EPCs from hypertensivepatients and normotensive patients. The in-vitro function, in-vivo reendothelialization capacity and GTPCH/BH4 pathway of human EPCs were evaluated. RESULTS: Both in-vitro function and reendothelialization capacity of EPCs were lower in hypertensivepatients than that in normotensive patients. The GTPCH/BH4 pathway of EPCs was downregulated in hypertensivepatients. Shear stress increased in-vitro function and reendothelialization capacity of EPCs from hypertensivepatients and normotensive patients. Furthermore, shear stress upregulated the expression of GTPCH I and levels of BH4, nitric oxide, and cGMP of EPCs, and reduced thrombospondin-1 expression. With treatment of GTPCH knockdown or nitroarginine methyl ester inhibition, shear stress-induced increased levels of BH4, nitric oxide and cGMP of EPCs was suppressed. When GTPCH/BH4 pathway of EPCs was blocked, the effects of shear stress on in-vitro function and reendothelialization capacity of EPCs were inhibited. CONCLUSION: The study demonstrates for the first time that shear stress-induced upregulation of the GTPCH/BH4 pathway ameliorates hypertension-related decline in endothelial repair capacity of EPCs. These findings provide novel nonpharmacologic therapeutic approach for hypertension-related endothelial repair.
Authors: Zhenhua Huang; Zhihao Liu; Keke Wang; Zi Ye; Yan Xiong; Bin Zhang; Jinli Liao; Lijing Zeng; Haitao Zeng; Gexiu Liu; Hong Zhan; Zhen Yang Journal: Front Cardiovasc Med Date: 2021-03-29