Differential Regulation of Human PlGF Gene Expression in Trophoblast and Nontrophoblast Cells by Oxygen Tension

Abstract

Objective-To determine the mechanism for differential effects of low oxygen tension on human PlGF gene transcription in trophoblast and nontrophoblast cells.Study Design-Human PlGF reporter clones and real time RT-PCR were used to compare the effects of hypoxia on gene transcription in human trophoblast and nontrophoblast cell lines. Overexpression of HIF-1α, inhibition of HIF-1 function and biochemical assessments of HIF-1 cofactor interactions were used to characterize hypoxia response mechanisms regulating PlGF transcription.Results-PlGF transcription is specifically inhibited by low oxygen tension in trophoblast but is induced in some nontrophoblast cells. Overexpression of HIF-1α in normoxic cells or inhibition of HIF-1 function in hypoxic cells did not significantly alter transcription patterns of the PlGF gene in either cell type.Conclusions-These results suggest that transcriptional repression of PlGF gene expression occurs in human trophoblast exposed to low oxygen tension but that PlGF transcription is stimulated in certain hypoxic nontrophoblast cells. However, regulation of PlGF transcription is not mediated by functional HIF-1 activity in either cell types.

Epigenetic control of hypoxia inducible factor-1α-dependent expression of placental growth factor in hypoxic conditions

“…No increase in histone acetylation was observed in promoter regions 4 and 5, where putative HREs, already reported by other authors, are present (not shown). 21,34 Surprisingly, a strong enrichment of H3 and H4 acetylation was instead observed in region 7, located in the second Plgf intron (P < 0.005 for histone H3 and P < 0.01 for histone H4, vs normoxic control) (Fig. 3B).…”

“…We Despite several reports indicate that hypoxia, as well as the overexpression of HIF-1α, are responsible in vitro and in vivo for a positive modulation of PlGF, 2,25-29 the direct involvement of the HIF transcriptional complex has not been evidenced with classical transcriptional studies on Plgf promoter. 21,24,34 Considering that it has recently been reported that epigenetic regulation of chromatin structure plays an important role in defining the response to hypoxia, 30 we decided to investigate the role of epigenetic modifications, such as DNA methylation and histone acetylation, in the modulation of PlGF expression under hypoxic stimuli.…”

Placental expression of the angiogenic placental growth factor is stimulated by both aldosterone and simulated starvation

“…The role of environmental conditions on PlGF expression in pregnancy is less clear. Upregulation of angiogenic factors, such as PlGF, in trophoblast seems not to be supported by hypoxia and hypoxia-induced factor-1α (14). As such, other regulatory pathways must be considered such as glucose availability, which might play a role in this process.…”

Heme-bound iron activates placenta growth factor in erythroid cells via erythroid Krüppel-like factor

“…Placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family [5][6][7][8][9] and plays important roles under physiological and pathological conditions. [10][11][12][13][14][15][16][17][18][19][20] We recently demonstrated that patients with SCD have elevated levels of PlGF and endothelin-1 (ET-1) and that enforced expression of PlGF in mice induces ET-1.…”