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Abstract
Aberrant, neovascular retinal blood vessel growth is a vision-threatening complication in ischemic retinal diseases. It is driven by retinal hypoxia frequently caused by capillary nonperfusion and endothelial cell (EC) loss. We investigated the role of EC apoptosis in this process using a mouse model of ischemic retinopathy, in which vessel closure and EC apoptosis cause capillary regression and retinal ischemia followed by neovascularization. Protecting ECs from apoptosis in this model did not prevent capillary closure or retinal ischemia. Nonetheless, it prevented the clearance of ECs from closed capillaries, delaying vessel regression and allowing ECs to persist in clusters throughout the ischemic zone. In response to hypoxia, these preserved ECs underwent a vessel sprouting response and rapidly reassembled into a functional vascular network. This alleviated retinal hypoxia, preventing subsequent pathogenic neovascularization. Vessel reassembly was not limited by VEGFA neutralization, suggesting it was not dependent on the excess VEGFA produced by the ischemic retina. Neutralization of ANG2 did not prevent vessel reassembly, but did impair subsequent angiogenic expansion of the reassembled vessels. Blockade of EC apoptosis may promote ischemic tissue revascularization by preserving ECs within ischemic tissue that retain the capacity to reassemble a functional network and rapidly restore blood supply.
Highlights
Angiogenesis is the growth of new blood vessels from preexisting vessels and occurs through a tightly regulated response of endothelial cells (ECs) to proangiogenic factors [1, 2]
Transient exposure of mice to high oxygen causes the apoptotic death of ECs and consequent regression of retinal capillaries in the center of the retina, resulting in relative retinal hypoxia once the mice are returned to room air oxygen levels
These results confirm the central role of the BCL2regulated apoptosis pathway in the apoptotic response of ECs in the oxygen-induced retinopathy (OIR) model
Summary
Angiogenesis is the growth of new blood vessels from preexisting vessels and occurs through a tightly regulated response of endothelial cells (ECs) to proangiogenic factors [1, 2]. While increased angiogenesis correlates with better outcomes in ischemic diseases like stroke [6], ischemia and the upregulation of VEGFA can drive aberrant angiogenesis, exacerbating certain diseases. This is evident in retinal diseases, such as proliferative diabetic retinopathy, retinal vein occlusion, and retinopathy of prematurity, in which aberrant angiogenesis (neovascularization) increases the risk of severe vision loss and blindness [7]. Current treatments for neovascular disease in the retina revolve around reducing the angiogenic stimulus either by decreasing the metabolic activity of the retina or by direct inhibition of VEGFA [8,9,10,11,12] While these approaches improve visual outcomes, many patients show either no response or a suboptimal response [8, 9].
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