This application proposes the continuation of a project designed to elucidate the mechanisms controlling pathological vascular growth during ischemic retinopathy. We have been studying the role in this process of nitric oxide synthase (NOS) and its product, NO, in regulating the expression and activity of vascular endothelial growth factor (VEGF). Our research with models of oxygen-induced retinopathy (OIR) and diabetes indicates that increased formation of NO, superoxide and their combination product peroxynitrite contribute to the over expression of VEGF and the associated vascular pathology in ischemic retinopathy. We now propose to identify specific molecular mediators of these effects. Recent clinical and experimental findings have implicated increased angiotensin II (Ang II) activity in retinal VEGF over-expression, vascular hyperpermeability and neovascularization in diabetes and OIR. Ang II is known to cause endothelial cell dysfunction in various forms of cardiovascular disease by increasing vascular NAD(P)H oxidase activity and superoxide anion formation. In macrovascular endothelial cells Ang II causes increases in expression and activity of NAD(P)H to generate superoxide. Superoxide is thought to induce """"""""uncoupling"""""""" of eNOS to generate superoxide as:well as NO, resulting in peroxynitrite formation. Our preliminary data suggest that retinal neovascularization during OIR is associated with increased vascular expression and activity of the NAD(P)H oxidase subunit gp91phox which is correlated with increased formation of superoxide and peroxynitrite. This suggests that superoxide production via NAD(P)H oxidase has a role in the vascular pathology. Using endothelial cells from bovine retina we have found that peroxynitrite formation is associated with activation of the VEGF transcription regulator STAT3 and increased expression of VEGF. Based on these observations, we hypothesize that retinal neovascularization during ischemic retinopathy critically involves activation of NAD(P)H oxidase via Ang II, leading to eNOS """"""""uncoupling"""""""", peroxynitrite formation and VEGF over-expression.
Our specific aims are to test this hypothesis by using established cell biology approaches and both in vitro and in vivo models in experiments designed to answer the following questions: 1) Does retinal ischemia cause over-expression of VEGF and neovascularization via activation of NAD(P)H oxidase? 2) Is peroxynitrite formation increased during ischemia via the action of NAD(P)H oxidase-derived superoxide in causing eNOS """"""""uncoupling""""""""? 3) Does retinal ischemia activate NAD(P)H oxidase and induce over-expression of VEGF and neovascularization via Ang II? 4) Do hypoxia and Ang II increase vascular expression of VEGF via peroxynitrite-mediated activation of STAT3?
| Rojas, Modesto A; Shen, Zu T; Caldwell, Ruth B et al. (2018) Blockade of TREM-1 prevents vitreoretinal neovascularization in mice with oxygen-induced retinopathy. Biochim Biophys Acta Mol Basis Dis 1864:2761-2768 |
| Shosha, Esraa; Xu, Zhimin; Narayanan, S Priya et al. (2018) Mechanisms of Diabetes-Induced Endothelial Cell Senescence: Role of Arginase 1. Int J Mol Sci 19: |
| Fouda, Abdelrahman Y; Xu, Zhimin; Shosha, Esraa et al. (2018) Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses. Cell Death Dis 9:1001 |
| Chandra, Surabhi; Fulton, David J R; Caldwell, Ruth B et al. (2018) Hyperglycemia-impaired aortic vasorelaxation mediated through arginase elevation: Role of stress kinase pathways. Eur J Pharmacol 844:26-37 |
| Zhang, Hanfang; Hudson, Farlyn Z; Xu, Zhimin et al. (2018) Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization. Invest Ophthalmol Vis Sci 59:2520-2528 |
| Caldwell, R William; Rodriguez, Paulo C; Toque, Haroldo A et al. (2018) Arginase: A Multifaceted Enzyme Important in Health and Disease. Physiol Rev 98:641-665 |
| Rojas, Modesto; Lemtalsi, Tahira; Toque, Haroldo A et al. (2017) NOX2-Induced Activation of Arginase and Diabetes-Induced Retinal Endothelial Cell Senescence. Antioxidants (Basel) 6: |
| Toque, Haroldo A; Fernandez-Flores, Aracely; Mohamed, Riyaz et al. (2017) Netrin-1 is a novel regulator of vascular endothelial function in diabetes. PLoS One 12:e0186734 |
| Bhatta, Anil; Yao, Lin; Xu, Zhimin et al. (2017) Obesity-induced vascular dysfunction and arterial stiffening requires endothelial cell arginase 1. Cardiovasc Res 113:1664-1676 |
| Yao, Lin; Bhatta, Anil; Xu, Zhimin et al. (2017) Obesity-induced vascular inflammation involves elevated arginase activity. Am J Physiol Regul Integr Comp Physiol 313:R560-R571 |
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