Immunolocalization of the vasoconstrictor endothelin in human endometrium during the menstrual cycle and in umbilical cord at birth

doi:10.1016/S0002-9378(11)91652-4

American Journal of Obstetrics and Gynecology

Volume 167, Issue 1, July 1992, Pages 163-167

https://doi.org/10.1016/S0002-9378(11)91652-4 Get rights and content

Objective: Our objective was to determine the localization of immunoreactive endothelin in human cyclic endometrium and in umbilical cord during normal delivery and after cesarean section.

Study Design: Fixed dated endometrial tissue (n = 41) and umbilical cord (n = 6) were subjected to immunohistochemistry with an antiserum cross reacting with endothelin-1, −2 and −3.

Results: Low levels of stromal endometrial staining were seen throughout the cycle. The strongest staining was in luminal epithelium throughout the secretory phase and in glandular epithelium in the late-secretory phase. In umbilical cord the most intense immunoreactivity was present on the amnion cells on the outer cord, with some staining in intermittent cells in the Wharton's jelly and in umbilical vein cells. No differences were detected between cord from normal delivery or cesarean section.

Conclusion: A paracrine role is suggested for endothelin in regulation of endometrial function and a role in vasoconstriction in the umbilical cord at birth.

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Endothelin is rapidly induced after tissue injury and is a potent vasoconstrictor. Endothelin expression varies along the menstrual cycle peaking in glandular cells during the perimenstrual phase (Marsh et al., 1996; Ohbuchi et al., 1995; Salamonsen et al., 1992). Endothelin receptor B is also increased in stromal and glandular cells during menstruation (Collett et al., 1996).
During the reproductive life, the human endometrium undergoes cycles of substantial remodeling including, at menstruation, a massive but delimited tissue breakdown immediately followed by scarless repair. The present review aims at summarizing the current knowledge on the endocrine and paracrine control of menstruation in the light of recent observations that undermine obsolete dogmas. Menstruation can be globally considered as a response to falling progesterone concentration. However, tissue breakdown is heterogeneous and tightly controlled in space and time by a complex network of regulators and effectors, including cytokines, chemokines, proteases and various components of an inflammatory response. Moreover, menstruation must be regarded as part of a complex and integrated mechanism of tissue remodeling including features that precede and follow tissue lysis, i.e. decidualization and immediate post-menstrual regeneration. The understanding of the regulation of menstruation is of major basic and clinical interest. Indeed, these mechanisms largely overlap with those controlling other histopathological occurrences of tissue remodeling, such as development and cancer, and inappropriate control of menstrual features is a major potential cause of two frequent endometrial pathologies (i.e. abnormal uterine bleeding and endometriosis).
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It is therefore a likely inducer of expression of these MMPs upon progesterone withdrawal at menstruation. The potent vasoconstrictor endothelin is maximally expressed in glandular cells during the perimenstrual phase and TGF-β1 and IL-1α induce its expression [8, 74–76]. Endothelin receptor B is also increased in stromal and glandular cells during menstruation [77].
When abundant and activated, matrix metalloproteinases (MMPs, or matrixins) degrade most, if not all, constituents of the extracellular matrix (ECM). The resulting massive tissue breakdown is best exemplified in humans by the menstrual lysis and shedding of the endometrium, the mucosa lining the uterus. After menstruation, MMP activity needs to be tightly controlled as the endometrium regenerates and differentiates to avoid abnormal tissue breakdown while allowing tissue repair and fine remodelling to accommodate implantation of a blastocyst. This paper reviews how MMPs are massively present and activated in the endometrium at menstruation, and how their activity is tightly controlled at other phases of the cycle. Progesterone represses expression of many but not all MMPs. Its withdrawal triggers focal expression of MMPs specifically in the areas undergoing lysis, an effect mediated by local cytokines such as interleukin-1α, LEFTY-2, tumour necrosis factor-α and others. MMP-3 is selectively expressed at that time and activates proMMP-9, otherwise present in latent form throughout the cycle. In addition, a large number of neutrophils loaded with MMPs are recruited at menstruation through induction of chemokines, such as interleukin-8. At the secretory phase, progesterone repression of MMPs is mediated by transforming growth factor-β. Tissue inhibitors of metalloproteinases (TIMPs) are abundant at all phases of the cycle to prevent any undue MMP activity, but are likely overwhelmed at menstruation. At other phases of the cycle, MMPs can elude TIMP inhibition as exemplified by recruitment of active MMP-7 to the plasma membrane of epithelial cells, allowing processing of membrane-associated growth factors needed for epithelial repair and proliferation. Finally, receptor-mediated endocytosis through low density lipoprotein receptor-related protein-1 (LRP-1) efficiently clears MMP-2 and -9 at the proliferative and secretory phases. This mechanism is probably essential to prevent any excessive ECM degradation by the active form of MMP-2 that is permanently present. However, shedding of the ectodomain of LRP-1 specifically at menstruation prevents endocytosis of MMPs allowing full degradation of the ECM. Thus endometrial MMPs are regulated at the levels of transcription, release from infiltrating neutrophils, activation, binding to the cell membrane, inhibition by TIMPs and endocytic clearance by LRP-1. This allows tight control during endometrial growth and differentiation but results in a burst of activity for menstrual tissue breakdown. This article is part of a Special Issue entitled: Proteolysis 50 years after the discovery of lysosome.
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This study was undertaken to study vascular reactivity of small myometrial arteries in women with idiopathic menorrhagia.
Small myometrial arteries were isolated from 6 patients with idiopathic menorrhagia and 4 controls. The contractile responses to thromboxane mimetic (U46619) and endothelin-1 were assessed before and after incubation with N^w-nitro-L arginine methyl ester alone or in combination with indomethacin (Indo). Endothelium-dependent dilation to bradykinin and basal tension were compared before and after incubation with N^w-nitro-L arginine methyl ester alone, or with N^w-nitro-L arginine methyl ester in combination with indomethacin.
Constriction to endothelin-1 was enhanced in idiopathic menorrhagia arteries (P < .05). Idiopathic menorrhagia arteries demonstrated enhanced basal tension after incubation with N^w-nitro-L arginine methyl ester, which was further exaggerated by indomethacin. NOS inhibition had no effect on basal tension in controls, but basal tension was enhanced after inhibition of cyclooxygenase-derived products (P < .05). Bradykinin-mediated dilation was significantly increased in idiopathic menorrhagia (P < .05).
The presence of functional alterations in small myometrial arteries could contribute to idiopathic menorrhagia.
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The potent vasoconstrictor endothelin-1 (ET-1) may function as a neuropeptide and be a contributing factor in some neurological disorders, e.g. Alzheimer’s dementia. The presence of ET-1 has been studied more extensively in the rat and porcine nervous systems than in the human brain. Also, the recent description of the extensive ET-1 mRNA localisation in human neural tissue supports expression in regions of human brain not previously investigated. Using specific anti-ET-1 polyclonal antiserum, we immunolocalised ET-1 in 24 regions of human brain autopsy tissues, and correlated this with ET-1 mRNA distribution. ET-1 immunoreactivity was observed within some cells of all the 24 areas examined. Neuronal staining for ET-1 was demonstrated within the diencephalon, brainstem, basal nuclei, cerebral cortex, cerebellar hemisphere, amygdala and hippocampus. In addition, ET-1 immunolabelling was visualised in the pituitary gland as well as in the choroid plexus. The primary sensory cortex and pineal gland also contained immunoreactive ET-1, although ET-1 mRNA had never been detected in these regions previously. The localisation of ET-1 and its subsequent correlation with ET-1 mRNA in most of the regions investigated suggest a more extensive distribution of the ET system in the human brain than was previously identified.
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¹: Supported by the National Health and Medical Research Council of Australia and by the World Health Organization Special Programme of Research, Development and Research Training in Human Reproduction.

^a: From Prince Henry's Institute of Medical Research, Monash University

^b: Department of Obstetrics and Gynaecology, Monash University.

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Immunolocalization of the vasoconstrictor endothelin in human endometrium during the menstrual cycle and in umbilical cord at birth1

FEBS Lett

FEBS Lett

Mol Cell Endocrinol

FEBS Lett

Biochim Biophys Acta

Regulation of polypeptide growth factor synthesis and growth factor—related gene expression in the rat and mouse uterus before and after implantation

J Reprod Fertil

Paracrine regulation of implantation and uterine function

Paracrine interactions amongst cells of the endometrium

A novel potent vasoconstrictor peptide produced by vascular endothelial cells

Nature

Localization of en-dothelin-like immunoreactivity in airway epithelium of rats and mice

J Pathol

Distribution of en-dothelin-like immunoreactivity and mRNA in the developing and adult human lung

Am J Respir Cell Mol Biol

Immunolocalization, binding and biological activity of endothelin in rabbit uterus, effect of ovarian steroids

Am J Phvsio!