The Experts below are selected from a list of 121422 Experts worldwide ranked by ideXlab platform

Phillip J Bridges - One of the best experts on this subject based on the ideXlab platform.

  • why two Endothelins and two receptors for ovulation and luteal regulation
    Life Sciences, 2012
    Co-Authors: Rina Meidan, Phillip J Bridges
    Abstract:

    The ovary is a dynamic organ that undergoes cyclic structural and functional changes. Structurally, the internal architecture of the ovary constantly changes as follicles grow, rupture and transform into corpora lutea in a cyclical manner. Functionally, a variety of regulatory ovarian hormones are sequentially produced, and eggs are periodically released. As a highly vascularized organ, the ovarian structures and functions change in response to external stimuli that include but are not limited to pituitary gonadotropins. Following stimulation, the ovary synthesizes and releases autocrine and paracrine signals that play unique roles in regulating its function. Recent studies have identified Endothelins as local regulators in the ovary that modulate multiple cyclic events, such as follicle growth, steroidogenesis, oocyte maturation, ovulation, corpus luteum formation and luteolysis. Interestingly, in all mammalian species examined to date, a common observation has been made: the ovary produces two pharmacologically similar Endothelins (ET-1 and ET-2) but expresses two functionally different endothelin receptors (ETA and ETB) that often give rise to opposite physiological outcomes following activation by an endothelin. In this review, the physiological significance of the presence of the two ligand-two receptor endothelin system in the ovary will be discussed.

  • Endothelins in regulating ovarian and oviductal function
    Frontiers in Bioscience, 2011
    Co-Authors: Phillip J Bridges, Jongki Cho
    Abstract:

    In the last 30 years, remarkable progress has been made in our understanding of the biological role of Endothelins in the regulation of reproductive function and fertility. A peptide hormone identified for its ability to regulate blood pressure has now been shown as a potent mediator of several reproductive pathways. Ligand- and receptor-specific roles have been identified and/or postulated during follicular development and ovulation as well as in the function and regression of the corpus luteum. In this review we have attempted to organize endothelin-mediated ovarian processes in a process-specific manner, rather than compile a review of ligand- or isoform-specific actions. Further, we have included a discussion on "post-ovarian" or oviductal function, as well as the future directions that we believe will increase our understanding of endothelin biology as a whole.

  • identification of a novel role for Endothelins within the oviduct
    Endocrinology, 2010
    Co-Authors: Myoungkun Jeoung, Sungeun Lee, Hee Kyung Hawng, Yongpil Cheon, Youn Kyung Jeong, Myung Chan Gye, Marc Iglarz, Phillip J Bridges
    Abstract:

    Endothelins were first identified as potent vasoactive peptides; however, diversity in the biological function of these hormones is now evident. We have identified a novel role for Endothelins: a requirement for these peptides within the oviduct during fertilization and/or early embryo development. In vivo, treatment after ovulation with a dual endothelin receptor antagonist (tezosentan) decreased the number of two-cell embryos that could be collected from within the oviducts. In vitro fertilization experiments showed that gamete viability and their ability to fertilize were not affected by treatment with this antagonist, suggesting that the effect observed in vivo was mediated by the oviduct itself. Expression of mRNA for all three isoforms of the Endothelins and both receptor subtypes was detectable within the oviduct. Expression of mRNA for endothelin-3 was regulated by gonadotropins in epithelial cells of the oviduct and increased specifically within the isthmus of this structure. Immunostaining revea...

Matthew J Grimshaw - One of the best experts on this subject based on the ideXlab platform.

  • Endothelins and hypoxia inducible factor in cancer
    Endocrine-related Cancer, 2007
    Co-Authors: Matthew J Grimshaw
    Abstract:

    The endothelin system is a family of three similar small peptides, two G-protein-coupled receptors and two proteinases. Endothelins have several physiological roles, notably in embryonic differentiation and vascular homeostasis. Numerous types of tumour express Endothelins and their regulation is often aberrant when compared with the normal tissue from which the tumour arose. However, endothelin expression is tumour-type specific, and in some instances, expression of individual members of the endothelin system will be upregulated, while in other tumour types, they may be downregulated. Endothelins have numerous potential roles in tumours including modulating angiogenesis, inducing mitogenesis and invasion of tumour cells, and protecting cells from apoptosis. Expression of Endothelins is controlled by the tumour microenvironment, whilst the Endothelins themselves modify that environment; a case in point is that hypoxia stimulates endothelin expression via hypoxia-inducible factor (HIF)-1, while Endothelins stabilise HIF-1 leading to expression of, for instance, vascular endothelial growth factor. This review highlights the potential roles of Endothelins in various cancers and describes the pre-clinical and clinical progress that has been made in several tumour types - notably prostate, ovary, melanoma and breast cancer. The interactions between the endothelin network and HIF-1 are highlighted.

  • Endothelins induce ccr7 expression by breast tumor cells via endothelin receptor a and hypoxia inducible factor 1
    Cancer Research, 2006
    Co-Authors: Julia Wilson, Joy M Burchell, Matthew J Grimshaw
    Abstract:

    Endothelin expression is increased in breast tumors and is associated with invasion and metastasis, whereas CCR7 expression by breast tumor cells may have a role in the organ specificity of breast cancer spread. In this article, we have analyzed whether Endothelins influence breast tumor cell expression of the chemokine receptor CCR7. Stimulation of human breast tumor cell lines with Endothelins increased cell surface expression of CCR7 via endothelin receptor A. The iron chelators desferrioxamine and cobalt chloride, which induce hypoxia-inducible factor (HIF)-mediated transcription, also increased CCR7 expression; transfection of a dominant-negative version of the HIF regulatory subunit, HIF-1α, into MCF-7 cells abolished CCR7 induction by Endothelins, indicating that increased expression is due to HIF-1 stabilization. Endothelin stimulation promoted invasion toward the CCR7 ligands CCL19 and CCL21. Endothelin-mediated chemokine-independent invasion itself is dependent on CCR7 activity and could be abolished using a CCR7-neutralizing monoclonal antibody. In human breast carcinomas, mRNA expression of Endothelins correlated with the level of CCR7 expression, both of which were associated with the presence of lymph node metastases. Expression of the CCR7 ligands CCL19 and CCL21 was also higher in breast cancer patients with lymph node involvement compared with those without, but expression of these chemokines did not correlate with endothelin expression. These data show that CCR7 may be regulated by the breast tumor microenvironment and further support the use of endothelin receptor antagonists in the treatment of invasive and metastatic breast cancer. (Cancer Res 2006; 66(24): 11802-7)

  • Endothelins in breast tumour cell invasion
    Cancer Letters, 2005
    Co-Authors: Matthew J Grimshaw
    Abstract:

    Abstract Endothelins are a family of small, structurally related, vasoactive peptides that have a great number of physiological roles in many tissues. The ‘endothelin axis’ consists of three 21 amino acid peptides (ET-1, ET-2 and ET-3), two G-protein-coupled receptors (ET-RA and ET-RB), and two activating peptidases or endothelin-converting enzymes (ECE-1 and ECE-2). There is increased expression of the endothelin axis in invasive breast cancer compared to the normal breast or non-invasive neoplastic tissue. Endothelin expression is associated with invading regions of tumours in patient biopsies and is more common in tumours with high histological grade and lymphovascular invasion, and there is increased systemic endothelin in patients with lymph node metastases compared to those without lymph node involvement. Stimulation of breast tumour cell lines with Endothelins leads to an invasive phenotype in vitro. Over-expression of the Endothelins and their receptors is insufficient to induce an invasive phenotype in benign cells, yet expression by tumour cells leads to markedly increased invasive ability indicating that Endothelins act in concert with other factors—both autocrine and paracrine—including cytokines, matrix metalloproteinases and the activation of tumour-associated macrophages. The association between Endothelins, poor prognosis and invasion may mean that the endothelin axis is a valid therapeutic target for the treatment of invasive breast cancer. This review summarises our current knowledge of Endothelins in breast cancer invasion and discusses the potential further directions of such research as well as the possibility of anti-endothelin-based therapy of breast cancer.

Mark Sullivan - One of the best experts on this subject based on the ideXlab platform.

  • Endothelins erectile dysfunction
    Pharmacological Research, 2011
    Co-Authors: Robert Ritchie, Mark Sullivan
    Abstract:

    Abstract Erectile dysfunction (ED) is common and a significant contributor to poor quality of life and psychosocial morbidity in men. Normal erectile function requires effective co-ordination between a number of complex neural pathways. Penile tumescence occurs in response to rapid arterial inflow to the corpora cavernosa with simultaneous venous outflow restriction due to expansion of the lacunar spaces. This process is under both central and local neuromediation. Endothelins are potent vasoconstrictor peptides that cause strong, slowly developing but sustained contraction of trabecular smooth muscles cells of the corpora cavernosa. Multiple mechanisms of action are proposed, including transmembrane calcium flux, mobilisation of inositol triphosphate sensitive intracellular calcium stores and calcium sensitisation through the Rho-Rho kinase pathway. The exact role of Endothelins in the pathogenesis of ED currently remains unclear. Elevated endothelin-1 levels are found in patients with diabetes mellitus and this alone may be sufficient to cause ED. However, this is not borne out in clinical studies. The resultant elevated intracellular calcium may, however, modulate gene expression sufficiently to cause smooth muscle proliferation. Alternatively, alterations in endothelin receptor sensitivity in conditions such as diabetes and hypertension may enhance vasoconstrictor processes. Currently there is contradictory evidence for the role of endothelin receptor antagonists in ED. Animals studies suggest they inhibit corporal vasoconstriction, improve erectile function and protect against diabetes-induced smooth muscle apoptosis. However, the results of clinical studies in ED have been less promising. Uncertainty regarding the exact role of endothelin in penile erection hampers progress in this area. It is possible that the endothelin system may only be relevant to ED in certain conditions where global endothelial dysfunction exists (e.g. diabetes mellitus, systemic sclerosis) and the use of endothelin antagonists in these patient groups may yield improved outcomes.

David J. Webb - One of the best experts on this subject based on the ideXlab platform.

  • Endothelins in cardiovascular biology and therapeutics
    Nature Reviews Cardiology, 2019
    Co-Authors: Neeraj Dhaun, David J. Webb
    Abstract:

    Cardiovascular disease is a major contributor to global morbidity and mortality and is the common end point of many chronic diseases. The Endothelins comprise three structurally similar peptides of 21 amino acids in length. Endothelin 1 (ET-1) and ET-2 activate two G protein-coupled receptors — endothelin receptor type A (ETA) and endothelin receptor type B (ETB) — with equal affinity, whereas ET-3 has a lower affinity for ETA. ET-1 is the most potent vasoconstrictor in the human cardiovascular system and has remarkably long-lasting actions. ET-1 contributes to vasoconstriction, vascular and cardiac hypertrophy, inflammation, and to the development and progression of cardiovascular disease. Endothelin receptor antagonists have revolutionized the treatment of pulmonary arterial hypertension. Clinical trials continue to explore new applications of endothelin receptor antagonists, particularly in treatment-resistant hypertension, chronic kidney disease and patients receiving antiangiogenic therapies. Translational studies have identified important roles for the endothelin isoforms and new therapeutic targets during development, in fluid-electrolyte homeostasis, and in cardiovascular and neuronal function. Novel pharmacological strategies are emerging in the form of small-molecule epigenetic modulators, biologics (such as monoclonal antibodies for ETB) and possibly signalling pathway-biased agonists and antagonists. Endothelin 1 is the most potent vasoconstrictor in the human cardiovascular system. In this Review, Dhaun and Webb discuss the biology of the Endothelins and endothelin receptors and how these pathways can be therapeutically targeted in cardiovascular and renal diseases.

  • Endothelin.
    Pharmacological Reviews, 2016
    Co-Authors: Anthony P Davenport, David J. Webb, Neeraj Dhaun, Kelly A Hyndman, Christopher Southan, Donald E Kohan, Jennifer S Pollock, David M Pollock, Janet J Maguire
    Abstract:

    The Endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

  • The Clinical Potential of Endothelin Receptor Antagonists in Cardiovascular Medicine
    Drugs, 1996
    Co-Authors: Charles J. Ferro, David J. Webb
    Abstract:

    The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET_A and ET_B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ETB receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the Endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud’s disease. There are now a number of selective ET_A and combined ET_A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.

Anthony P Davenport - One of the best experts on this subject based on the ideXlab platform.

  • Endothelin.
    Pharmacological Reviews, 2016
    Co-Authors: Anthony P Davenport, David J. Webb, Neeraj Dhaun, Kelly A Hyndman, Christopher Southan, Donald E Kohan, Jennifer S Pollock, David M Pollock, Janet J Maguire
    Abstract:

    The Endothelins comprise three structurally similar 21-amino acid peptides. Endothelin-1 and -2 activate two G-protein coupled receptors, ETA and ETB, with equal affinity, whereas endothelin-3 has a lower affinity for the ETA subtype. Genes encoding the peptides are present only among vertebrates. The ligand-receptor signaling pathway is a vertebrate innovation and may reflect the evolution of endothelin-1 as the most potent vasoconstrictor in the human cardiovascular system with remarkably long lasting action. Highly selective peptide ETA and ETB antagonists and ETB agonists together with radiolabeled analogs have accurately delineated endothelin pharmacology in humans and animal models, although surprisingly no ETA agonist has been discovered. ET antagonists (bosentan, ambrisentan) have revolutionized the treatment of pulmonary arterial hypertension, with the next generation of antagonists exhibiting improved efficacy (macitentan). Clinical trials continue to explore new applications, particularly in renal failure and for reducing proteinuria in diabetic nephropathy. Translational studies suggest a potential benefit of ETB agonists in chemotherapy and neuroprotection. However, demonstrating clinical efficacy of combined inhibitors of the endothelin converting enzyme and neutral endopeptidase has proved elusive. Over 28 genetic modifications have been made to the ET system in mice through global or cell-specific knockouts, knock ins, or alterations in gene expression of endothelin ligands or their target receptors. These studies have identified key roles for the endothelin isoforms and new therapeutic targets in development, fluid-electrolyte homeostasis, and cardiovascular and neuronal function. For the future, novel pharmacological strategies are emerging via small molecule epigenetic modulators, biologicals such as ETB monoclonal antibodies and the potential of signaling pathway biased agonists and antagonists.

  • anatomical localization and pharmacological activity of mature Endothelins and their precursors in human vascular tissue
    Journal of Hypertension, 1992
    Co-Authors: Paisley G Howard, C Plumpton, Anthony P Davenport
    Abstract:

    OBJECTIVES We developed four selective rabbit antisera in order to compare the distribution of immunoreactive mature Endothelins and their precursors, proendothelin-1, proendothelin-2 and proendothelin-3, in the endothelium from human vascular tissue. Our second aim was to use in vitro pharmacological assays to test the vasoconstrictor actions of the mature endothelin and proendothelin peptides. METHODS The antisera were shown to be selective by enzyme-linked immunosorbent assays. With these antisera, we detected immunoreactivity in serial cryostat sections from saphenous and mesenteric veins, and mesenteric and internal mammary arteries, using a peroxidase-antiperoxidase technique. In pharmacological experiments, segments of human coronary and mesenteric arteries were exposed to cumulative (0.06-60 nmol/l) concentrations of the Endothelins and their precursors. RESULTS Antisera directed against mature endothelin stained the cytoplasm of endothelial cells in all vessels tested. Immunoreactive proendothelin-1 and proendothelin-2 were also detected, but not proendothelin-3. Endothelin-1 and endothelin-2 were strongly vasoactive, with similar molar potencies, and caused a dose-related increase in contractile force in human coronary arteries (0.06-60 nmol/l). However, proendothelin-1 and proendothelin-2 were 100-fold and 1000-fold less vasoactive than their respective mature peptides. No contractile effect was seen with proendothelin-3 or endothelin-3 at the concentrations tested in human coronary arteries, and similar results were obtained with human mesenteric arteries. CONCLUSIONS These results suggest that proendothelin-1 and proendothelin-2 must be converted to their corresponding mature peptides to produce vasoconstrictor activity in human vessels. Immunoreactive mature endothelin is widely distributed in human vascular endothelial cells and, if released, may produce endothelin-mediated vasoconstriction.