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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY018420-03
Application #
7747971
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Shen, Grace L
Project Start
2008-01-01
Project End
2010-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
3
Fiscal Year
2010
Total Cost
$329,670
Indirect Cost
Name
Scott and White Memorial Hospital
Department
Type
DUNS #
076697960
City
Temple
State
TX
Country
United States
Zip Code
76504
Costa, Isabel A S F; Hein, Travis W; Gamperl, A K (2015) Cold-acclimation leads to differential regulation of the steelhead trout (Oncorhynchus mykiss) coronary microcirculation. Am J Physiol Regul Integr Comp Physiol 308:R743-54
Thengchaisri, Naris; Hein, Travis W; Ren, Yi et al. (2015) Endothelin-1 impairs coronary arteriolar dilation: Role of p38 kinase-mediated superoxide production from NADPH oxidase. J Mol Cell Cardiol 86:75-84
Hein, Travis W; Rosa Jr, Robert H; Ren, Yi et al. (2015) VEGF Receptor-2-Linked PI3K/Calpain/SIRT1 Activation Mediates Retinal Arteriolar Dilations to VEGF and Shear Stress. Invest Ophthalmol Vis Sci 56:5381-9
Costa, Isabel A S F; Hein, Travis W; Secombes, Christopher J et al. (2015) Recombinant interleukin-1? dilates steelhead trout coronary microvessels: effect of temperature and role of the endothelium, nitric oxide and prostaglandins. J Exp Biol 218:2269-78
Potts, Luke B; Bradley, Patrick D; Xu, Wenjuan et al. (2013) Role of endothelium in vasomotor responses to endothelin system and protein kinase C activation in porcine retinal arterioles. Invest Ophthalmol Vis Sci 54:7587-94
Hein, Travis W; Xu, Wenjuan; Ren, Yi et al. (2013) Cellular signalling pathways mediating dilation of porcine pial arterioles to adenosine A?A receptor activation. Cardiovasc Res 99:156-63
Potts, Luke B; Ren, Yi; Lu, Guangrong et al. (2012) Constriction of retinal arterioles to endothelin-1: requisite role of rho kinase independent of protein kinase C and L-type calcium channels. Invest Ophthalmol Vis Sci 53:2904-12
Nakabayashi, Seigo; Nagaoka, Taiji; Tani, Tomofumi et al. (2012) Retinal arteriolar responses to acute severe elevation in systemic blood pressure in cats: role of endothelium-derived factors. Exp Eye Res 103:63-70
Hein, Travis W; Potts, Luke B; Xu, Wenjuan et al. (2012) Temporal development of retinal arteriolar endothelial dysfunction in porcine type 1 diabetes. Invest Ophthalmol Vis Sci 53:7943-9
Hein, Travis W; Ren, Yi; Potts, Luke B et al. (2012) Acute retinal ischemia inhibits endothelium-dependent nitric oxide-mediated dilation of retinal arterioles via enhanced superoxide production. Invest Ophthalmol Vis Sci 53:30-6

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