Mol. Hum. Reprod. Advance Access originally published online on April 28, 2006
Molecular Human Reproduction 2006 12(6):367-375; doi:10.1093/molehr/gal027
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Expression and regulation of vascular endothelial growth factor ligands and receptors during menstruation and post-menstrual repair of human endometrium
1Research Institute for Growth and Development (GROW), 2Department of Pathology and 3Department of Obstetrics and Gynaecology, University Hospital Maastricht and University Maastricht, Maastricht, The Netherlands
4 To whom correspondence should be addressed at: Philips Research, High Tech Campus 4 WAG 11, 5656 AA Eindhoven, The Netherlands. E-mail: chamindie.punyadeera{at}philips.com
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 HIF1
and CA-IX in the menstrual and early proliferative phases. HIF1 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.
Key words: angiogenesis/ECM/gene-expression profiling/human endometrium/hypoxia/menstrual cycle/neuropilin/estrogen/VEGF and VEGF receptor
* These authors contributed equally to this work.
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