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(American Journal of Pathology. 2001;158:1399-1410.)
© 2001 American Society for Investigative Pathology

Regular Articles

Vascular Repair After Menstruation Involves Regulation of Vascular Endothelial Growth Factor-Receptor Phosphorylation by sFLT-1

Michael D. Graubert^*, Maria Asuncion Ortega, Bruce Kessel^*, Joseph F. Mortola^* and M. Luisa Iruela-Arispe

From the Department of Obstetrics and Gynecology,^*
Division of Reproductive Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and the Department of Molecular, Cell, and Developmental Biology and the Molecular Biology Institute,
University of California–Los Angeles, Los Angeles, California

Regeneration of the endometrium after menstruation requires a rapid and highly organized vascular response. Potential regulators of this process include members of the vascular endothelial growth factor (VEGF) family of proteins and their receptors. Although VEGF expression has been detected in the endometrium, the relationship between VEGF production, receptor activation, and endothelial cell proliferation during the endometrial cycle is poorly understood. To better ascertain the relevance of VEGF family members during postmenstrual repair, we have evaluated ligands, receptors, and activity by receptor phosphorylation in human endometrium throughout the menstrual cycle. We found that VEGF is significantly increased at the onset of menstruation, a result of the additive effects of hypoxia, transforming growth factor-, and interleukin-1ß. Both VEGF receptors, FLT-1 and KDR, followed a similar pattern. However, functional activity of KDR, as determined by phosphorylation studies, revealed activation in the late menstrual and early proliferative phases. The degree of KDR phosphorylation was inversely correlated with the presence of sFLT-1. Endothelial cell proliferation analysis in endometrium showed a peak during the late menstrual and early proliferative phases in concert with the presence of VEGF, VEGF receptor phosphorylation, and decrease of sFLT-1. Together, these results suggest that VEGF receptor activation and the subsequent modulation of sFLT-1 in the late menstrual phase likely contributes to the onset of angiogenesis and endothelial repair in the human endometrium.

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