TY - JOUR
T1 - 1,25(OH)2D3 induces placental vascular smooth muscle cell relaxation by phosphorylation of myosin phosphatase target subunit 1Ser507
T2 - Potential beneficial effects of vitamin d on placental vasculature in humans
AU - Jia, Xiuyue
AU - Gu, Yang
AU - Groome, Lynn J.
AU - Al-Kofahi, Mahmoud
AU - Alexander, J. Steven
AU - Li, Weimin
AU - Wang, Yuping
N1 - Publisher Copyright:
© 2016 by the Society for the Study of Reproduction, Inc.
PY - 2016/5
Y1 - 2016/5
N2 - 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 downregulated, and CYP24A1 expression was dose-dependently upregulated 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-MYPT1Thr853 and p-MYPT1Thr696 were undetectable. However, p-MYPT1Ser507, but not p-MYPT1Ser668, was significantly upregulated 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 MYPT1Ser507 phosphorylation could be a mechanism of vitamin D and/or losartan mediated placental VSMC relaxation.
AB - 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 downregulated, and CYP24A1 expression was dose-dependently upregulated 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-MYPT1Thr853 and p-MYPT1Thr696 were undetectable. However, p-MYPT1Ser507, but not p-MYPT1Ser668, was significantly upregulated 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 MYPT1Ser507 phosphorylation could be a mechanism of vitamin D and/or losartan mediated placental VSMC relaxation.
KW - MYPT1
KW - VSMC contractility
KW - placenta
KW - pregnancy
KW - vitamin D
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U2 - 10.1095/biolreprod.116.138362
DO - 10.1095/biolreprod.116.138362
M3 - Article
C2 - 27075619
AN - SCOPUS:84977117552
SN - 0006-3363
VL - 94
JO - Biology of reproduction
JF - Biology of reproduction
IS - 5
M1 - 116
ER -