title: Shear stress-mediated upregulation of GTP cyclohydrolase/tetrahydrobiopterin pathway ameliorates hypertension-related decline in reendothelialization capacity of endothelial progenitor cells.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.affiliation: 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.
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Bai
authors.forename: Songhua
authors.initials: S
authors.lastname: Xiao
authors.forename: Yong-Bo
authors.initials: YB
authors.lastname: Tang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Tan
authors.forename: Hailin
authors.initials: H
authors.lastname: Tang
authors.forename: Zhi
authors.initials: Z
authors.lastname: Ren
authors.forename: Haitao
authors.initials: H
authors.lastname: Zeng
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yang
mesh_terms: D000818:Animals; D001708:Biopterins / Q000031:analogs & derivatives* / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D015536:Down-Regulation; D066026:Endothelial Progenitor Cells / Q000502:physiology*; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D051379:Mice; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D013314:Stress, Mechanical; D019700:Thrombospondin 1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D019700:Thrombospondin 1; D001708:Biopterins; D009569:Nitric Oxide; D006136:GTP Cyclohydrolase; C003402:sapropterin; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester