Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium

C Punyadeera, V L Thijssen, S Tchaikovski, R Kamps, B Delvoux, G A J Dunselman, A F P M de Goeij, A W Griffioen, P G Groothuis

Research output: Contribution to journalArticleAcademicpeer-review

55 Citations (Scopus)


Regeneration and growth of the human endometrium after shedding of the functional layer during menstruation depends on an adequate angiogenic response. We analysed the mRNA expression levels of all known vascular endothelial growth factor (VEGF) ligands and receptors in human endometrium collected in the menstrual and proliferative phases of the menstrual cycle. In addition, we evaluated the expression of VEGF-A, VEGF-R2 and NRP-1 at the protein level. Two periods of elevated mRNA expression of ligands and receptors were observed, separated by a distinct drop at cycle days (CDs) 9 and 10. Immunohistochemical staining showed that VEGF and VEGF-R2 were expressed in epithelial, stromal and endothelial cells. NRP-1 was mainly confined to stroma and blood vessels; only in late-proliferative endometrium, epithelial staining was also observed. Except for endothelial VEGF-R2 expression in CDs 6-8, there were no significant differences in the expression of VEGF, VEGF-R2 or NRP-1 in any of the cell compartments. In contrast, VEGF release by cultured human endometrium explants decreased during the proliferative phase. This output was significantly reduced in menstrual and early-proliferative endometrium by estradiol (E2) treatment. Western blot analysis indicated that part of the VEGF-A was trapped in the extracellular matrix (ECM). Changes in VEGF ligands and receptors were associated with elevated expression of the hypoxia markers HIF1alpha and CA-IX in the menstrual and early proliferative phases. HIF1alpha was also detected in late-proliferative phase endometrium. Our findings indicate that VEGF-A exerts its actions mostly during the first half of the proliferative phase. Furthermore, VEGF-A production appears to be triggered by hypoxia in the menstrual phase and subsequently suppressed by estrogen during the late proliferative phase.

Original languageEnglish
Pages (from-to)367-75
Number of pages9
JournalMolecular Human Reproduction
Issue number6
Publication statusPublished - Jun 2006


  • Adult
  • Blotting, Western
  • Carbonic Anhydrases/genetics
  • Endometrium/chemistry
  • Female
  • Gene Expression/genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit/genetics
  • Immunohistochemistry
  • Menstrual Cycle/genetics
  • Menstruation/genetics
  • Middle Aged
  • Neuropilin-1/genetics
  • RNA, Messenger/genetics
  • Receptors, Vascular Endothelial Growth Factor/genetics
  • Reverse Transcriptase Polymerase Chain Reaction
  • Vascular Endothelial Growth Factor A/genetics
  • Vascular Endothelial Growth Factor Receptor-1/genetics
  • Vascular Endothelial Growth Factor Receptor-2/genetics

Cite this