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      The Role of the Endothelin System in the Vascular Dysregulation Involved in Retinitis Pigmentosa

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          Abstract

          Retinitis pigmentosa is a clinical and genetic group of inherited retinal disorders characterized by alterations of photoreceptors and retinal pigment epithelium leading to a progressive concentric visual field restriction, which may bring about severe central vision impairment. Haemodynamic studies in patients with retinitis pigmentosa have demonstrated ocular blood flow abnormalities both in retina-choroidal and in retroocular vascular system. Moreover, several investigations have studied the augmentation of endothelin-1 plasma levels systemically in the body and locally in the eye. This might account for vasoconstriction and ischemia, typical in vascular dysregulation syndrome, which can be considered an important factor of reduction of the ocular blood flow in subjects affected by retinitis pigmentosa.

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          Most cited references71

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          Interaction of endothelin-3 with endothelin-B receptor is essential for development of epidermal melanocytes and enteric neurons.

          Defects in the gene encoding the endothelin-B receptor produce aganglionic megacolon and pigmentary disorders in mice and humans. We report that a targeted disruption of the mouse endothelin-3 ligand (EDN3) gene produces a similar recessive phenotype of megacolon and coat color spotting. A natural recessive mutation that results in the same developmental defects in mice, lethal spotting (ls), failed to complement the targeted EDN3 allele. The ls mice carry a point mutation of the EDN3 gene, which replaces the Arg residue at the C-terminus of the inactive intermediate big EDN3 with a Trp residue. This mutation prevents the proteolytic activation of big EDN3 by ECE-1. These findings indicate that interaction of EDN3 with the endothelin-B receptor is essential in the development of neural crest-derived cell lineages. We postulate that defects in the human EDN3 gene may cause Hirschsprung's disease.
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            Targeted and natural (piebald-lethal) mutations of endothelin-B receptor gene produce megacolon associated with spotted coat color in mice.

            Endothelins act on two subtypes of G protein-coupled receptors, termed endothelin-A and endothelin-B receptors. We report a targeted disruption of the mouse endothelin-B receptor (EDNRB) gene that results in aganglionic megacolon associated with coat color spotting, resembling a hereditary syndrome of mice, humans, and other mammalian species. Piebald-lethal (sl) mice exhibit a recessive phenotype identical to that of the EDNRB knockout mice. In crossbreeding studies, the two mutations show no complementation. Southern blotting revealed a deletion encompassing the entire EDNRB gene in the sl chromosome. A milder allele, piebald (s), which produces coat color spotting only, expresses low levels of structurally intact EDNRB mRNA and protein. These findings indicate an essential role for EDNRB in the development of two neural crest-derived cell lineages, myenteric ganglion neurons and epidermal melanocytes. We postulate that defects in the human EDNRB gene cause a hereditary form of Hirschsprung's disease that has recently been mapped to human chromosome 13, in which EDNRB is located.
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              The primary vascular dysregulation syndrome: implications for eye diseases

              Vascular dysregulation refers to the regulation of blood flow that is not adapted to the needs of the respective tissue. We distinguish primary vascular dysregulation (PVD, formerly called vasospastic syndrome) and secondary vascular dysregulation (SVD). Subjects with PVD tend to have cold extremities, low blood pressure, reduced feeling of thirst, altered drug sensitivity, increased pain sensitivity, prolonged sleep onset time, altered gene expression in the lymphocytes, signs of oxidative stress, slightly increased endothelin-1 plasma level, low body mass index and often diffuse and fluctuating visual field defects. Coldness, emotional or mechanical stress and starving can provoke symptoms. Virtually all organs, particularly the eye, can be involved. In subjects with PVD, retinal vessels are stiffer and more irregular, and both neurovascular coupling and autoregulation capacity are reduced while retinal venous pressure is often increased. Subjects with PVD have increased risk for normal-tension glaucoma, optic nerve compartment syndrome, central serous choroidopathy, Susac syndrome, retinal artery and vein occlusions and anterior ischaemic neuropathy without atherosclerosis. Further characteristics are their weaker blood–brain and blood-retinal barriers and the higher prevalence of optic disc haemorrhages and activated astrocytes. Subjects with PVD tend to suffer more often from tinnitus, muscle cramps, migraine with aura and silent myocardial ischaemic and are at greater risk for altitude sickness. While the main cause of vascular dysregulation is vascular endotheliopathy, dysfunction of the autonomic nervous system is also involved. In contrast, SVD occurs in the context of other diseases such as multiple sclerosis, retrobulbar neuritis, rheumatoid arthritis, fibromyalgia and giant cell arteritis. Taking into consideration the high prevalence of PVD in the population and potentially linked pathologies, in the current article, the authors provide recommendations on how to effectively promote the field in order to create innovative diagnostic tools to predict the pathology and develop more efficient treatment approaches tailored to the person.
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                Author and article information

                Journal
                J Ophthalmol
                J Ophthalmol
                JOPH
                Journal of Ophthalmology
                Hindawi Publishing Corporation
                2090-004X
                2090-0058
                2015
                3 November 2015
                : 2015
                : 405234
                Affiliations
                1Department of Surgical Sciences, Unit of Ophthalmology, Ospedale Maggiore, Bologna, Italy
                2Department of Biomedical and Surgical Sciences, Section of Human Physiology, University of Ferrara, 44100 Ferrara, Italy
                3Department of Biomedical and Surgical Sciences, Division of Ophthalmology, University of Ferrara, 44100 Ferrara, Italy
                Author notes
                *Francesco Saverio Sorrentino: fra.sorrentino@ 123456gmail.com

                Academic Editor: Suphi Taneri

                Article
                10.1155/2015/405234
                4647052
                dc7e0c28-b984-49c1-a909-bae97785a039
                Copyright © 2015 Francesco Saverio Sorrentino et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 23 August 2015
                : 18 October 2015
                Categories
                Review Article

                Ophthalmology & Optometry
                Ophthalmology & Optometry

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