Abstract
Ocular neovascularization is a comprehensive process involved in retinal vascular development and several blinding diseases such as age-related macular degeneration and retinopathy of prematurity, with vascular endothelial growth factor (VEGF) regarded as the master regulator. However, the qualified effect of anti-VEGF therapy reveals that the underlying mechanisms are still not clearly identified. To initialize angiogenesis, endothelial cells undergo a phenotype switching to generate highly migratory and invasive cells. This process shares certain similar characters observed in endothelial–mesenchymal transition (EndMT). Here, we found that SNAI1, an EndMT transcription factor, was expressed by endothelial cells in both physiological and pathological ocular neovascularization. SNAI1 overexpression triggered cell morphological change and enhanced cell motility, while loss of SNAI1 attenuated migration, invasion and sprouting. RNA sequence analysis further revealed that SNAI1 knockdown decreased the expression of genes related to cytoskeleton rearrangement and ECM remodeling. Moreover, intravitreal injection of small interfering RNA of SNAI1 suppressed new vessel formation in developing retina as well as mice model of choroidal neovascularization and oxygen-induced retinopathy. Therefore, we propose that the EndMT transcription factor SNAI1 promotes the early phase of ocular neovascularization and may provide a potential therapeutic target.
Highlights
Ocular angiogenesis is a highly coordinated process involved in retinal vasculature development and several ocular diseases such as age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) [1, 2]
◂Fig. 6 RNA sequence analysis showed that SNAI1 knockdown decreased genes involved in cytoskeleton arrangement, extracellular matrix (ECM) degrading and remodeling. a GSEA results revealed “Rac1 pathway” and “Rho pathway” enriched in negative control (NC) compared to siSNAI1-transfected cells. b GSEA results revealed genes related to “ECM disassembly” and “invasiveness” enriched in NC compared to siSNAI1-transfected cells
Heat map displayed the expression of typical regulated genes involved in ECM degradation. c GSEA results revealed genes related to “ECM component” and “ECM structural constituent” enriched in NC compared to siSNAI1-transfected cells
Summary
Ocular angiogenesis is a highly coordinated process involved in retinal vasculature development and several ocular diseases such as age-related macular degeneration (AMD), proliferative diabetic retinopathy (PDR) and retinopathy of prematurity (ROP) [1, 2]. ECs begin to proliferate, invade and migrate along components of the extracellular matrix (ECM) and take part in the formation of an immature capillary structure and deposition of a new complex BM [4] This process involves complex and highly dynamic interactions between ECs and their environment [5]. During angiogenesis, activated ECs act more invasively compared to quiescent phase, including formation of lamellipodia and filopodia, degradation of BM, migration into ECM and participation in ECM remodeling These functional changes share several similarities with endothelial–mesenchymal transition (EndMT), in which process ECs undergo a phenotype switching to generate elongated, spindle-shaped mesenchymal-like cells which are highly migratory and invasive [9,10,11]. We further tested its function under VEGF stimulus and evaluated its therapeutic potential as well
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