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Role of Endothelin System and NAD(P)H Oxidase in Retinal Arteriolar Dysfunction

内皮素系统和 NAD(P)H 氧化酶在视网膜小动脉功能障碍中的作用

基本信息

批准号：
7539150
负责人：
TRAVIS W HEIN
金额：
$ 33.3万
依托单位：
SCOTT AND WHITE MEMORIAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-01-01 至 2012-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7539150
关键词：
Acetylcholine Acute Address Affect Agonist Angle-Closure Glaucoma Animal Welfare Bibliography Biological Availability Blindness Blood Vessels Blood flow Bradykinin Brain Country Diabetic Retinopathy Disease Endothelin Endothelin B Receptor Endothelin Receptor Endothelin-1 Endothelin-converting enzyme 1 Endothelium Environment Environmental Impact Enzyme Inhibitor Drugs Enzyme Inhibitors Equipment Event Family suidae Functional disorder Future Goals Heart IACUC Impairment In Vitro International Ischemia Lead Link MAPK14 gene Mediating Mitogen-Activated Protein Kinases Mitogens Modality Modeling Molecular Neurons Nitric Oxide Operative Surgical Procedures Oxidases Oxidative Stress Pathogenesis Pathway interactions Physiologic Intraocular Pressure Physiological Pilot Projects Principal Investigator Production Protein Kinase Protein Kinase C Proteins Reactive Oxygen Species Regulation Relative (related person)Research Research Ethics Committees Resources Retina Retinal Retinal Vascular Occlusion Retinopathy of Prematurity Rho-associated kinase Role Series Signal Pathway Signal Transduction Site Smooth Muscle Source Superoxides System Techniques Testing Therapeutic Intervention Vascular Diseases Vasoconstrictor Agents Vasodilation Vasodilator Agents Vasomotor Vertebrates Visual impairment abstracting arteriole citrate carrier constriction endothelin-converting enzyme expiration human MAPK14 protein human subject in vivo novel phosphoramidon prevent programs receptor research study retinal damage retinal ischemia rho tempol vasoconstriction

项目摘要

DESCRIPTION (provided by applicant): Acute periods of retinal ischemia impair subsequent supply of retinal blood flow and have been associated with several ocular diseases leading to visual impairment and blindness. Experimental evidence of diminished retinal blood flow after the initial retinal ischemia suggests that endothelial dysfunction may contribute to persistent retinal damage. Two important endothelium-derived factors involved in regulating retinal blood flow are vasodilator nitric oxide (NO) and vasoconstrictor endothelin-1 (ET-1). Our preliminary studies showed that retinal ischemia via elevated intraocular pressure (IOP) impaired bradykinin-induced NO-mediated dilation and enhanced ET-1-mediated constriction in pig retinal arterioles. Intravitreal administration of superoxide scavenger TEMPOL or endothelin-converting enzyme (ECE) inhibitor phosphoramidon before ischemia preserved vasodilation to bradykinin. Although these pilot studies suggest the involvement of ET-1 and oxidative stress in vascular dysfunction, their interrelationship and the signaling events contributing to the observed impairment remain to be elucidated. Herein, we hypothesize that ischemic insult activates the protein kinase C (PKC)-dependent vascular endothelin system, which leads to superoxide production via NAD(P)H oxidase and a subsequent increase in Rho/Rho kinase activation for the increased vascular tone and a reduced NO-mediated vasodilation. Since our long-term goal is to understand the signaling mechanisms responsible for physiological and pathophysiological regulation of retinal vasomotor function leading to future vascular therapy, the present application will serve the initial step toward this goal by identifying the causal factor and cellular mechanisms contributing to the impairment of vascular function following acute retinal ischemia. We will test the aforementioned hypothesis by pursuing three specific aims: (1) Determine whether enhanced ECE and PKC activities contribute to ischemia-induced dysfunction of retinal arterioles. (2) Determine whether activation of endothelin A/B receptors and vascular p38 mitogen-activated protein kinase/NAD(P)H oxidase signaling contributes to ischemia-induced dysfunction of retinal arterioles. (3) Determine whether enhanced vascular Rho/Rho kinase signaling contributes to ischemia-induced dysfunction of retinal arterioles. We will use both in-vivo and in-vitro approaches with various cellular/molecular techniques to integrate these three aims for elucidating the underlying mechanisms and signaling pathways responsible for the ischemia-induced arteriolar dysfunction in the retina. The results derived from these studies are essential to advance our understanding in the pathogenesis of retinal vascular disease associated with retinal ischemia and may suggest novel targets for future therapeutic interventions. Reduction in normal blood flow or ischemia to the retina in the eye has been associated with several ocular diseases leading to visual impairment and blindness. Experimental evidence of diminished retinal blood flow after the initial retinal ischemia suggests that reduction in the ability of small blood vessels, the arterioles, to widen or dilate by producing or responding to the chemical nitric oxide may contribute to persistent damage of the retina. A potential mechanism leading to the impairment of blood vessel function is elevated levels of endothelin in the retina. Endothelin is a protein that can impact blood vessels by causing them to collapse or constrict, or by increasing the production of oxygen-derived free radicals, which can damage nitric oxide. However, the precise roles of and potential link between these two events in contributing to this abnormal function of retinal vessels following retinal ischemia remain unknown. The goal of this proposal is to gain a better understanding into the mechanisms leading to the functional damage of the small blood vessels in the retina, which will be helpful for development of new therapies for retinal ischemic disease.