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

Abstract

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-1␤. 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 The cyclic regeneration of the endometrium during the female reproductive years requires a highly regulated angiogenic response.1-5 Physiological changes associated with loss and reconstruction of the functional endometrium during the menstrual cycle are unique to the higher primate species. Humans undergo shedding of the upper spongy layer of the endometrium during menses. 4,6,7 Menstrual bleeding itself is brought on by tissue breakdown and damage surrounding superficial endometrial vessels. Within 5 days of menstrual onset, the damaged endometrial vessels have been repaired. 8 Hence, the initial phase of endometrial angiogenesis involves repair of the vascular bed in concert with the late stages of menstrual shedding and during the proliferative phase. Models of endometrial angiogenesis in the proliferative phase describe the growth of the vasculature under the influence of estrogen, whereas the secretory phase involves growth of the coiled arterioles mediated by progesterone.

Regulation of endometrial vascular remodelling: role of the vascular endothelial growth factor family and the angiopoietin–TIE signalling system

“…If such vasoconstriction occurred in the endometrium in situ, it would provide a possible mechanism for vessel repair through hypoxia-induced upregulation of VEGFA. Several studies have observed the highest expression of VEGFA during the menstrual phase of the menstrual cycle (CharnockJones et al 1993, Sharkey et al 2000, Graubert et al 2001. In addition, more SLC2A1 (a glucose transporter and marker of anaerobic metabolism that is induced by ischaemia, previously known as GLUT1) was found in endometrial samples from menstruating women in comparison to proliferative or secretory phase samples (Graubert et al 2001).…”

“…VEGFA mRNA and protein are expressed by both the epithelium and stroma of the primate and rodent endometrium, with temporal and spatial changes apparent during the menstrual cycle (Charnock-Jones et al 1993, Shifren et al 1996, Torry et al 1996, Sharkey et al 2000, Graubert et al 2001, Lee et al 2008. The expression patterns reported are not consistent and are therefore difficult to interpret.…”

“…The expression patterns reported are not consistent and are therefore difficult to interpret. However, several studies do report the highest expression of VEGFA during the menstrual phase of the cycle (Charnock-Jones et al 1993, Sharkey et al 2000, Graubert et al 2001.…”

“…Several studies have observed the highest expression of VEGFA during the menstrual phase of the menstrual cycle (CharnockJones et al 1993, Sharkey et al 2000, Graubert et al 2001. In addition, more SLC2A1 (a glucose transporter and marker of anaerobic metabolism that is induced by ischaemia, previously known as GLUT1) was found in endometrial samples from menstruating women in comparison to proliferative or secretory phase samples (Graubert et al 2001). High levels of VEGFA mRNA were observed in the glands, stroma and necrotic areas of menstrual phase endometrium (Charnock-Jones et al 1993, Sharkey et al 2000.…”

Vascular endothelial growth factor-A isoform and (co)receptor expression are differentially regulated by 17β-oestradiol in the ovariectomised mouse uterus

“…In vitro studies have demonstrated that E 2 increased the expression of VEGFA mRNA in a dose-and timedependent manner in cultured human endometrial stromal (Zhang et al 1995, Bausero et al 1998, Huang et al 1998, Graubert et al 2001) and epithelial cells (Zhang et al 1995) and in isolated endometrial endothelial cells (Shifren et al 1996). In vivo research with various animal models has produced more variable results.…”