Pathophysiologic mechanisms of ocular angiogenesis and modulation of the IGF1 system in pigs
Abstract
Ischemic retinopathies, such as diabetic retinopathy, are the most common cause of acquired blindness in the United States. Within the eye, retinal ischemia likely leads to soluble growth factor release and angiogenesis. This dissertation suggests that the insulin-like growth factor-1 (IGF1) system is a key regulator in retinal microvascular disease and ocular neovascularization (NV). We used a domestic pig model of preretinal and optic nerve head NV induced by photodynamic venous thrombosis to invariably produce pathologic NV. Permanent venous obstruction were created using an argon laser to occlude branch retinal veins following intravenous rose bengal injection, achieving ${\geq}50\%$ retinal ischemia. The degree of ocular angiogenesis was semi-quantitatively graded. Intravitreal triamcinolone significantly reduces this neovascular response. This BVO technique used in miniature pigs showed that NV plateaus between 3-6 months. We showed that the normal pig vitreous contained IGF1 and IGFBP2. After BVO, vitreous IGFBP2 levels increased by 3 days and were maintained for 1 month. Vitreous IGF1 increased one week postBVO and returned to normal between 1-3 months. IGFBP2 mRNA was localized to the perivascular, inner retina post-BVO. Intravitreal injection of 600$\mu$g hrIGF1 one week postBVO increased vitreous IGFBP2 levels and enhanced the neovascular response through 6 months. HrIGF1 injections also increased vitreous IGF1 levels, but they returned to baseline by 3 months postBVO. Intravitreal injection of 600$\mu$g hrIGF1 in normal domestic pig eyes created a retinal microangiopathy: vascular permeability, retinal arterial tortuosity, microaneurysm formation, increased EC density, decreased pericyte density, and increased capillary basement membranes thickness. HrIGF1 injection increased vitreous IGF1 and IGFBP2 levels for 1 month.
Degree
Ph.D.
Advisors
Harris, Purdue University.
Subject Area
Pathology|Anatomy & physiology|Animals|Animal diseases|Ophthalmology
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