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Hypoxia in Human Trophoblasts Stimulates the Expression and Secretion of Connective Tissue Growth Factor

Departments of Obstetrics and Gynecology (E.R., B.C., A.L.S., D.M.N., Y.S.) and Cell Biology and Physiology (E.R., B.C., Y.S.), Washington University School of Medicine, St. Louis, Missouri 63110

Address all correspondence to: Yoel Sadovsky, M.D., Magee-Womens Research Institute, 204 Craft Avenue, Pittsburgh, Pennsylvania 15213. E-mail: ysadovsky{at}mwri.magee.edu.

The mechanisms underlying cellular injury when human placental trophoblasts are exposed to hypoxia are unclear. Connective tissue growth factor (CTGF) mediates cell injury and fibrosis in diverse tissues. We hypothesized that hypoxia enhances the production of CTGF in primary term human trophoblasts. Using cultured term primary human trophoblasts as well as villous biopsies from term human placentas, we showed that CTGF protein is expressed in trophoblasts. When compared with cells cultured in standard conditions (FiO₂ = 20%), exposure of primary human trophoblasts to low oxygen concentration (FiO₂ = 8% or 1%) enhanced the expression of CTGF mRNA in a time-dependent manner, with a significant increase in CTGF levels after 16 h (2.7 ± 0.7-fold; P < 0.01), reaching a maximum of 10.9 ± 3.2-fold at 72 h. Whereas exposure to hypoxia had no effect on cellular CTGF protein levels, secretion of CTGF to the medium was increased after 16 h in hypoxia and remained elevated through 72 h. The increase in cellular CTGF transcript levels and CTGF protein secretion was recapitulated by exposure of trophoblasts to agents that enhance the activity of hypoxia-inducible factor (HIF)1, including cobalt chloride or the proline hydroxylase inhibitor dimethyloxaloylglycine, and attenuated using the HIF1 inhibitor 2-methoxyestradiol. Although all TGFβ isoforms stimulated the expression of CTGF in trophoblasts, only the expression of TGFβ1 mRNA was enhanced by hypoxia. We conclude that hypoxia increases cellular CTGF mRNA levels and CTGF protein secretion from cultured trophoblasts, likely in a HIF1-dependent manner.

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