Neutrophils infiltrating the endometrium express vascular endothelial growth factor: potential role in endometrial angiogenesis

Mueller, Michael D.; Lebovic, Dan I.; Garrett, Evelyn N.; Taylor, Robert N.

doi:10.1016/s0015-0282(00)00555-0

Cited by 117 publications

(75 citation statements)

References 22 publications

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“…30 Moreover, VEGF produced by local PMN (this study, Gargett et al 25 and Muller et al 63 ) could enhance PMN influx in an autocrine fashion, participate in monocyte recruitment, and increase vascular permeability during the inflammatory process associated with menstruation. 59 Neutrophil-derived elastase and other proteinases, secreted together with VEGF, could facilitate degradation of vascular basement membranes and of the subendothelial matrix, also contributing to the menstruation.…”

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confidence: 66%

“…59 Neutrophil-derived elastase and other proteinases, secreted together with VEGF, could facilitate degradation of vascular basement membranes and of the subendothelial matrix, also contributing to the menstruation. [62][63][64] As anti-inflammatory drugs block numerous PMN secretions, 31,34 including proteases and cytokines secretion, the therapeutic effect of nonsteroidal anti-inflammatory drugs in abnormal uterine bleeding 65 could be explained by the roles of PMN in human endometrium remodeling.…”

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confidence: 99%

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Vascular endothelial growth factor VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism

Ancelin

Chollet‐Martin

Hervé

et al. 2004

Laboratory Investigation

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Vascular endothelial growth factor (VEGF) is a potent and specific endothelial cell mitogen involved in normal and pathological angiogenesis. Our group recently reported that, among the several VEGF isoforms, VEGF189 (V189) is selectively induced in decidual endometrial cells during the mid-late phase of the menstrual cycle, together with polymorphonuclear neutrophil (PMN) influx. We thus compared the effects of various VEGF isoforms on PMN migration in vitro, and the mechanisms involved. In transmigration and under-agarose assays, V189 was both chemotactic and chemokinetic for PMN, while VEGF165 (V165) was only chemokinetic. The chemokinetic effect of V189 for PMN was blocked by neutralizing anti-VEGF antibodies, but not by neutralizing anti-KDR antibodies, suggesting that the Flt-1 VEGF receptor that is expressed in PMN mediates these effects. Flow cytometric analysis of several adhesion molecules at the PMN surface showed that all VEGF isoforms slightly upregulated b1-and b2-integrins and PECAM, and downregulated L-selectin; all these molecules are activation markers. The involvement of b1-integrins was further supported by the ability of blocking antibodies to reduce VEGF-induced PMN migration. As human PMN can secrete several cytokines and growth factors, the selective secretion of VEGF isoforms was also further examined. RT-PCR analysis showed that V165 mRNA was more strongly expressed than V189 mRNA. Conversely, the major protein isoform secreted after optimal PMN degranulation was V189, which was located in both azurophilic and specific granules. PMN-derived VEGF can thus modulate PMN migration. This autocrine amplification mechanism would allow sustained VEGF release to occur at inflammatory sites, and may contribute to both normal and pathological angiogenesis.

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confidence: 66%

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confidence: 99%

Vascular endothelial growth factor VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism

Ancelin

Chollet‐Martin

Hervé

et al. 2004

Laboratory Investigation

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“…It is likely that the major source of TGF-␣ and IL-1␤ in the endometrium is inflammatory cells, abundant in the menstrual endometrium, as compared to other phases of the cycle. 32 Induction of VEGF mRNA by IL-1␤ in vitro was doseand time-dependent, with a maximal 4.2-fold induction greater than control after a 4-hour incubation of human endometrial stromal cells with IL-1␤ (10 ng/ml) ( Figure 3, A and C). Incubation of endometrial stromal cells with TGF-␣ (50 ng/ml) throughout a 48-hour time course resulted in a maximal 2.1-fold induction of VEGF mRNA by 3 hours.…”

Section: Resultsmentioning

confidence: 93%

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

Graubert

Ortega

Kessel

et al. 2001

The American Journal of Pathology

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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.

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“…There was also a significant correlation between focal VEGF-expressing microvessels and proliferating vessels in all three regions of the endometrium (subepithelial capillary plexus, functionalis and basalis). The focal VEGF associated with microvessels was found to correspond to marginating and adherent neutrophils and it was hypothesised that these leukocytes provide a source of VEGF for the endometrial vessels undergoing proliferation (Mueller et al 2000.…”

Section: Introductionmentioning

confidence: 99%

Intravascular neutrophils partially mediate the endometrial endothelial cell proliferative response to oestrogen in ovariectomised mice

Heryanto¹,

Girling²,

Rogers³

2004

Reproduction

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The aim of this study was to investigate the role of intravascular neutrophils in initiating endothelial cell proliferation following oestrogen treatment in ovariectomised mouse endometrium. Uterine tissues were collected from ovariectomised C57/CBA female mice 24 h after oestrogen treatment with or without systemic neutrophil depletion. Neutropenia was achieved with either an in-house anti-neutrophil serum (ANS) or Gr-1 monoclonal antibody. All mice received an i.p. injection of bromodeoxyuridine (BrdU) 4 h prior to dissection to allow visualisation of proliferating cells using immunocytochemistry. Endometrial sections were immunostained for BrdU, vascular endothelial growth factor (VEGF), and neutrophils (using ANS). Oestrogen treatment of ovariectomised mice significantly increased the number of intravascular neutrophils, whereas induction of neutropenia with either ANS or Gr-1 in conjunction with oestrogen treatment prevented this increase. Oestrogen treatment of ovariectomised mice also significantly increased the number of intravascular VEGF-positive cells; however, whereas induction of neutropenia with ANS significantly reduced this increase, Gr-1 did not. In both studies, neutropenia significantly reduced, but did not eliminate, the amount of endometrial endothelial cell proliferation. These results suggest a role for neutrophils in endometrial angiogenesis following acute oestrogen treatment; however, the presence of VEGF-positive cells even after induction of neutropenia suggests that more than one type of leukocyte may be involved.

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Neutrophils infiltrating the endometrium express vascular endothelial growth factor: potential role in endometrial angiogenesis

Cited by 117 publications

References 22 publications

Vascular endothelial growth factor VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism

Vascular endothelial growth factor VEGF189 induces human neutrophil chemotaxis in extravascular tissue via an autocrine amplification mechanism

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

Intravascular neutrophils partially mediate the endometrial endothelial cell proliferative response to oestrogen in ovariectomised mice

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