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: firstname.lastname@example.org; Haitao Zeng, Center for Reproductive Medicine, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong, People's Republic of China. E-mail: email@example.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