PMID- 21349824
OWN - NLM
STAT- MEDLINE
DCOM- 20110926
LR  - 20151119
IS  - 1529-7268 (Electronic)
IS  - 0006-3363 (Linking)
VI  - 84
IP  - 6
DP  - 2011 Jun
TI  - Possible roles for folic acid in the regulation of trophoblast invasion and 
      placental development in normal early human pregnancy.
PG  - 1148-53
LID - 10.1095/biolreprod.110.088351 [doi]
AB  - In addition to its role in the prevention of neural tube defects, folic acid has 
      many other physiological functions, including cell proliferation, DNA 
      replication, and antioxidant protection. The aim of this study was to determine 
      the role that folic acid has in regulating placental trophoblast development. 
      Placental explants from placentae at gestational age 7 wk (n = 3) were cultured 
      in folic acid at concentrations of 10(-6) M, 10(-8) M, and 10(-10) M. 
      Extravillous trophoblast (EVT) invasion was assessed following 6-day culture, and 
      explants were used for immunohistochemical evaluation of proliferation (MKI67) 
      and apoptosis (active caspase 3). In addition, an array was performed on cell 
      culture supernatants to examine a range of matrix metalloproteinases (MMPs) and 
      tissue inhibitors of MMPs (TIMPs). Folic acid increased the invasion of EVT cells 
      in this explant model by between 83% and 19% (P = 0.005), and this was associated 
      with increased MKI67 positivity and decreased active caspase 3 positivity; this 
      effect was concentration dependent and showed a biphasic response. In addition, 
      culture in folic acid increased vascular density, as determined by anti-CD31 
      immunostaining (P = 0.05). The increase in EVT invasion correlated with increased 
      placental explant secretion of MMP2 (P = 0.01), MMP3 (P = 0.01), and MMP9 (P = 
      0.02). This study demonstrates that folic acid is potentially important in a 
      number of crucial early stages of placental development, including EVT invasion, 
      angiogenesis, and secretion of MMPs, and highlights the need for further studies 
      to address the benefit of longer-term folic acid supplementation throughout 
      pregnancy to prevent pregnancy disorders associated with deficient placental 
      development, including preeclampsia.
FAU - Williams, Paula J
AU  - Williams PJ
AD  - School of Clinical Sciences, University of Nottingham, City Hospital Nottingham, 
      United Kingdom. Paula.williams@nottingham.ac.uk
FAU - Bulmer, Judith N
AU  - Bulmer JN
FAU - Innes, Barbara A
AU  - Innes BA
FAU - Broughton Pipkin, Fiona
AU  - Broughton Pipkin F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110223
PL  - United States
TA  - Biol Reprod
JT  - Biology of reproduction
JID - 0207224
RN  - 0 (Tissue Inhibitor of Metalloproteinases)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Cells, Cultured
MH  - Embryo Implantation/*physiology
MH  - Female
MH  - Folic Acid/metabolism/*pharmacology
MH  - Gene Expression Regulation/physiology
MH  - Humans
MH  - Matrix Metalloproteinases/genetics/metabolism
MH  - *Placentation
MH  - Pregnancy
MH  - Tissue Inhibitor of Metalloproteinases/genetics/metabolism
MH  - Trophoblasts/*physiology
EDAT- 2011/02/26 06:00
MHDA- 2011/09/29 06:00
CRDT- 2011/02/26 06:00
PHST- 2011/02/26 06:00 [entrez]
PHST- 2011/02/26 06:00 [pubmed]
PHST- 2011/09/29 06:00 [medline]
AID - biolreprod.110.088351 [pii]
AID - 10.1095/biolreprod.110.088351 [doi]
PST - ppublish
SO  - Biol Reprod. 2011 Jun;84(6):1148-53. doi: 10.1095/biolreprod.110.088351. Epub 
      2011 Feb 23.