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Junyeop Lee, Akiyoshi Uemura, Gou Young Koh, Young Hee Yoon; Selective expression of angiopoietin-2 in pericyte-free endothelial cells is crucial for microaneurysm formation and vascular leakage.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2312. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Loss of retinal pericytes and subsequent formation of microaneurysms are the earliest structural changes in diabetic retinopathy. However, underlying mechanisms how the loss of retinal pericytes leads to endothelial proliferation and microaneurysm formation are yet to be clearly defined. The purposes of this study are to evaluate structural and functional changes of retinal vessels in the absence of pericytes, and to find out angiogenic growth factors associated with microaneurysm formation.
Using anti-PDGFRβ antibody, we have developed pericyte-deficient mouse model which follows sequential pathophysiological cascades of human diabetic retinopathy. Expressions of angiogenic genes were analyzed using transgenic reporter mice, in-situ hybridization, and immunofluorescence. To evaluate the role of angiopoietin-2 (Ang2) in microaneurysm formation, anti-Ang2 antibody was administrated into the vitreous of either eye in the pericyte-deficient mouse model.
We confirmed that systemic administration of anti-PDGFRβ antibody effectively induced pericyte dropout in the mouse retina. In this mouse, we observed microaneurysms, retinal hemorrhage and edema, which are characteristic findings of diabetic retinopathy. Ang2 is selectively expressed in pericyte-free endothelial cells of microaneurysms and new vessels in this mouse. VEGF-A promoted Ang2 expression in pericyte-free endothelial cells. When Ang2 is inhibited, new vessels and microaneurysms were markedly diminished even in the absence of pericytes. Blockade of Ang2 also effectively prevented retinal edema and hemorrhage in pericyte-deficient mouse model.
Loss of pericytes induces VEGF-A-mediated Ang2 expression in endothelial cells, which destabilize blood vessels leading to microaneurysm formation and vascular leakage. Therefore, Ang2 is crucial for the formation of microaneurysm and could be a direct therapeutic target inhibiting microaneurysm formation and retinal edema in diabetic retinopathy.
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