title: 1,25(OH)2D3 Induces Placental Vascular Smooth Muscle Cell Relaxation by Phosphorylation of Myosin Phosphatase Target Subunit 1Ser507: Potential Beneficial Effects of Vitamin D on Placental Vasculature in Humans.
abstract: Placental vascular dysfunction has been linked to insufficiency/deficiency of maternal vitamin D levels during pregnancy. In contrast, sufficient maternal vitamin D levels have shown beneficial effects on pregnancy outcomes. To study the role of vitamin D in pregnancy, we tested our hypothesis that vitamin D exerts beneficial effects on placental vasculature. We examined expression of CYP2R1, CYP27B1, vitamin D receptor (VDR), and CYP24A1 in placental vascular smooth muscle cells (VSMCs) in response to 1,25(OH)2D3 We found that VDR expression was inducible, CYP27B1 expression was dose-dependently down-regulated, and CYP24A1 expression was dose-dependently up-regulated in cells treated with 1,25(OH)2D3 These data suggest a feedback autoregulatory system of vitamin D existing in placental VSMCs. Using a VSMC/collagen-gel contraction assay, we evaluated the effect of 1,25(OH)2D3 on placental VSMC contractility. We found that, similar to losartan, 1,25(OH)2D3 could diminish angiotensin II-induced cell contractility. The mechanism of 1,25(OH)2D3-mediated VSMC relaxation was further explored by examination of Rho-associated protein kinase 1 (ROCK1)/phosphorylation of myosin phosphatase target subunit 1 (MYPT1) pathway molecules. Our results showed that p-MYPT1(Thr853) and p-MYPT1(Thr696) were undetectable. However, p-MYPT1(Ser507), but not p-MYPT1(Ser668), was significantly up-regulated in cells treated with losartan plus angiotensin II. Similar effects were also seen in cells treated with 1,25(OH)2D3 plus angiotensin II or 1,25(OH)2D3 plus losartan plus angiotensin II. Because MYPT1 serine phosphorylation could activate myosin light chain phosphatase (MLCP), and MLCP activation is an important regulatory machinery of smooth muscle cell relaxation, up-regulation of MYPT1(Ser507) phosphorylation could be a mechanism of vitamin D and/or losartan mediated placental VSMC relaxation.
authors.affiliation: Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana Department of Cardiology, The First Affiliated Hospital Harbin Medical University, Harbin, China.
authors.forename: Xiuyue
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gu
authors.affiliation: Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana.
authors.forename: Lynn J
authors.initials: LJ
authors.lastname: Groome
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana.
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Al-Kofahi
authors.affiliation: Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana.
authors.forename: J Steven
authors.initials: JS
authors.lastname: Alexander
authors.affiliation: Department of Cardiology, The First Affiliated Hospital Harbin Medical University, Harbin, China liweimin_2009@163.com.
authors.forename: Weimin
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana Department of Molecular and Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana ywang1@lsuhsc.edu.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Wang
mesh_terms: D002117:Calcitriol / Q000494:pharmacology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D043263:Myosin-Light-Chain Phosphatase / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D010920:Placenta / Q000166:cytology* / Q000187:drug effects; D011247:Pregnancy; D014664:Vasodilation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D043263:Myosin-Light-Chain Phosphatase; C490372:PPP1R12A protein, human; D002117:Calcitriol
keywords: MYPT1; VSMC contractility; placenta; pregnancy; vitamin D