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Shear stress-mediated upregulation of GTP cyclohydrolase/tetrahydrobiopterin pathway ameliorates hypertension-related decline in reendothelialization capacity of endothelial progenitor cells

Bai, Yong-Ping; Xiao, Songhua; Tang, Yong-Bo; Tan, Zhi; Tang, Hailin; Ren, Zhi; Zeng, Haitao; Yang, Zhen

doi: 10.1097/HJH.0000000000001216
ORIGINAL PAPERS: Pathophysiological aspects

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.

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

Correspondence to Zhen Yang, Department of Hypertension & Vascular Disease, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510080, Guangdong, People's Republic of China. E-mail: yangzhen10710710@163.com; Haitao Zeng, Center for Reproductive Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China. E-mail: zenghaitao@163.com

Abbreviations: BH4, tetrahydrobiopterin; cGMP, cyclic GMP; eNOS, endothelial nitric oxide synthase; EPC, endothelial progenitor cells; FPG, fasting plasma glucose; GTPCH I, GTP cyclohydrolase I; NO, nitric oxide; sGC, soluble guanylate cyclase; TC, total cholesterol; TG, triglyceride; TSP-1, thrombospondin-1

Received 20 January, 2016

Revised 11 October, 2016

Accepted 18 November, 2016

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