The long range goal of this project is to elucidate fundamental mechanisms of retinal angiogenesis. The overall hypothesis is that retinal angiogenesis depends on molecular interactions between the endothelial cell (EC) derived relaxing factor, nitric oxide (NO), its Ca2+-dependent synthetic enzyme, eNOS and the EC-specific angiogenic factor vascular endothelial growth factor (VEGF). A working model is proposed in which VEGF stimulation of its receptors induces NOS activation and production of NO, which influences EC growth directly by inducing cell proliferation and indirectly by inhibiting VEGF protein expression. This model will be developed and refined by experiments in specific aims designed to test the following specific hypotheses using a combination of cellular and molecular analytical approaches. 1) VEGF- induced growth of retinal ECs is mediated by eNOS production of NO. Experiments using cultured retinal Ecs will determine VEGF effects on NOS activity, NO production and cell growth in the presence and absence of NOS inhibitors and of NO onEC growth. 2) Expression of eNOS and VEGF is regulated by a feed-forward/feed-back relationship in which VEGF promotes increased eNOS expression and NO production which in turn inhibits VEGF expression. These experiments will test NO donor effects on VEGF expression in retinal Ecs and glial cells and VEGF effects on eNOS expression in retinal ECs. 3) eNOS is directly involved in VEGF signal transduction to the nucleus. These experiments will determine the effects of VEGF-stimulation on the subcellular distribution of eNOS, VEGF and its receptors and test the role of NO in VEGF-induction of gene transcription in retinal Ecs. 4) eNOS activity has a critical role in regulating retinal vascular growth and development in vivo. Experiments in eNOS deficient mice will characterize retinal vascular growth and development in relation to expression of inducible NOS (iNOS), constitutive NOS (nNOS) and VEGF. Information gained from these investigations will aid the development of therapies to prevent and control pathological angiogenic processes.
| 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 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 |
| 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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