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Taku Wakabayashi, Hisamichi Naito, Nobuyuki Takakura, Kohji Nishida; Roles of resident vascular endothelial stem-like cells in the development of ocular angiogenesis. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):3390.
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Ocular neovascular diseases, including diabetic retinopathy and the neovascular form of age-related macular degeneration (AMD) are the most common cause of severe vision loss worldwide. Since both retinal and choroidal neovascularization are caused by angiogenesis, further investigation of the mechanism of angiogenesis is warranted. The purpose of the present study is to newly identify the specific vascular endothelial cells (ECs) within the preexisting blood vessels which may play a central role in the initiation and development of angiogenesis.
We created the mice expressing GFP in the control of VEcadherin promoter by mating VEcadherin-Cre mouse and GFP reporter mouse carrying loxP sites. Mice organs (choroid, retina, brain, liver, lung, heart) were freshly isolated and single cell suspensions were prepared by enzymatic digestion. The specific vascular endothelial stem-like population was identified as side population (SP) cells by flow cytometric analysis based on the ability to efflux the DNA-binding dye, Hoechst 33342, via ATP-binding cassette (ABC) transporters.
In the choroid, 2.8% of GFP positive (VEcadherin positive) vascular ECs showed a typical SP staining pattern. They were not bone marrow-derived and possessed high colony-forming capacity in vitro. They proliferated and produced large number of ECs in vivo during laser-induced choroidal neovascularization. Microarray analysis revealed that vascular endothelial SP cells possess distinct molecular signature and establish a hierarchy of vascular endothelial cells. The SP cells with distinct molecular signature were also identified in the liver, lung, and heart. In contrast, stereotypic SP staining pattern was not observed in retinal and brain ECs due to highly expressed ABC transporters to maintain the blood-retinal barrier (BRB) or blood-brain barrier (BBB).
The vascular endothelial SP cells in the choroid may represent vessel-residing endothelial stem-like cells contributing mainly to angiogenesis, and may be useful for augmenting vascular regeneration or for developing new anti-angiogenic therapy in AMD.
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