title: Wnt5a attenuates hypoxia-induced pulmonary arteriolar remodeling and right ventricular hypertrophy in mice.
abstract: Hypoxic pulmonary hypertension (HPH), which is characterized by pulmonary arteriolar remodeling and right ventricular hypertrophy, is still a life-threatening disease with the current treatment strategies. The underlying molecular mechanisms of HPH remain unclear. Our previously published study showed that Wnt5a, one of the ligands in the Wnt family, was critically involved in the inhibition of hypoxia-induced pulmonary arterial smooth muscle cell proliferation by downregulation of β-catenin/cyclin D1 in vitro. In this study, we investigated the possible functions and mechanisms of Wnt5a in HPH in vivo. Recombinant mouse Wnt5a (rmWnt5a) or phosphate buffered saline (PBS) was administered to male C57/BL6 mice weekly from the first day to the end of the two or four weeks after exposed to hypoxia (10% O2). Hypoxia-induced pulmonary hypertension was associated with a marked increase in β-catenin/cyclin D1 expression in lungs. Right ventricular systolic pressure and right ventricular hypertrophy index were reduced in animals treated with rmWnt5a compared with PBS. Histology showed less pulmonary vascular remodeling and right ventricular hypertrophy in the group treated with rmWnt5a than with PBS. Treatment with rmWnt5a resulted in a concomitant reduction in β-catenin/cyclin D1 levels in lungs. These data demonstrate that Wnt5a exerts its beneficial effects on HPH by regulating pulmonary vascular remodeling and right ventricular hypertrophy in a manner that is associated with reduction in β-catenin/cyclin D1 signaling. A therapy targeting the β-catenin/cyclin D1 signaling pathway might be a potential strategy for HPH treatment.
authors.affiliation: Department of Physiology, Capital Medical University, Beijing 100069, P.R. China.
authors.forename: Yuling
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Physiology, Capital Medical University, Beijing 100069, P.R. China.
authors.forename: Wang
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Physiology, Capital Medical University, Beijing 100069, P.R. China.
authors.forename: Sanbao
authors.initials: S
authors.lastname: Chai
authors.affiliation: Department of Physiology, Capital Medical University, Beijing 100069, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100016, P.R. China wang_jun@ccmu.edu.cn dryangting@gmail.com.
authors.forename: Ting
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Physiology, Capital Medical University, Beijing 100069, P.R. China wang_jun@ccmu.edu.cn dryangting@gmail.com.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D019938:Cyclin D1 / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000209:etiology* / Q000503:physiopathology; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D066253:Vascular Remodeling / Q000187:drug effects / Q000502:physiology*; D051153:Wnt Proteins / Q000494:pharmacology / Q000502:physiology*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000502:physiology
chemical_list: C530105:Ccnd1 protein, mouse; D011994:Recombinant Proteins; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin; D019938:Cyclin D1
keywords: Hypoxic pulmonary hypertension; Wnt5a; pulmonary arteriolar remodeling; right ventricular hypertrophy