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Estrogen-Induced Vascular Endothelial Growth Factor A Expression in Luminal Epithelial Cells

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— 1 min read

Recent studies have shown that 17beta-estradiol (E-2) increases vascular endothelial growth factor A (Vegfa) gene expression in the rat uterus, leading to increased microvascular permeability. However, the specific site of this expression and the receptor through which E-2 triggers the signaling events leading to Vegfa expression were unclear. Investigators at the University of Maryland, Medical Department, have now addressed this question by examining the pathway regulating Vegfa expression in luminal epithelial (LE) cells isolated after E-2 treatment.

Key Takeaways:

  • E-2 stimulates Vegfa mRNA expression in LE cells, peaking at 1 h (4- to 14-fold) and returning to basal levels by 4 h.
  • Treatment with E-2 increases phosphorylation of AKT in LE cells, as well as of the downstream mediators FRAP1 (mTOR), GSK3B, and MDM2.
  • The alpha subunit of HIF1 (HIF1A) is present in LE cells before E-2 treatment and is unchanged 1 h after E-2, but is 2-fold higher by 4 h.
  • Chromatin immunoprecipitation analysis shows that HIF1A is recruited to the Vegfa promoter by 1 h and is absent again by 4 h.
  • The E-2 activation of the PI3K/AKT pathway, HIF1A recruitment to the Vegfa promoter, and Vegfa expression are all blocked by ICI 182,780, an ESR1 antagonist.
  • The rapid E-2-induced signaling events that lead to Vegfa expression occur in LE cells and appear to be initiated via a membrane form of ESR1.

Statistics:

  • E-2 increases Vegfa mRNA expression in LE cells by 4- to 14-fold 1 h after treatment.
  • The alpha subunit of HIF1 (HIF1A) is 2-fold higher in LE cells by 4 h after E-2 treatment.
  • Phosphorylation of AKT in LE cells, as well as of the downstream mediators FRAP1 (mTOR), GSK3B, and MDM2, is increased by E-2 treatment.
  • The PI3K/AKT pathway, HIF1A recruitment to the Vegfa promoter, and Vegfa expression are all blocked by ICI 182,780.

Sources:

  • A.A. Kazi et al. Estrogen Rapidly Activates the PI3K/AKT Pathway and Hypoxia-Inducible Factor 1 and Induces Vascular Endothelial Growth Factor A Expression in Luminal Epithelial Cells of the Rat Uterus. Biology of Reproduction, 2009;81(2):378-387.
  • R.D. Koos, University of Maryland, School Medical, Dept. of Physiol, 655 W Baltimore St., Baltimore, MD 21201, USA.
  • Society Study Reproduction, 1603 Monroe St., Madison, WI 53711-2021, USA.

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