MicroRNAs (miRNAs) modulate complex physiological and pathological processes by repressing expression of multiple components of cellular regulatory networks. Here we demonstrate that miRNAs encoded by the miR-23∼27∼24 gene clusters are enriched in endothelial cells and highly vascularized tissues. Inhibition of miR-23 and miR-27 function by locked nucleic acid-modified anti-miRNAs represses angiogenesis in vitro and postnatal retinal vascular development in vivo. Moreover, miR-23 and miR-27 are required for pathological angiogenesis in a laser-induced choroidal neovascularization mouse model. MiR-23 and miR-27 enhance angiogenesis by promoting angiogenic signaling through targeting Sprouty2 and Sema6A proteins, which exert antiangiogenic activity. Manipulating miR-23/ 27 levels may have important therapeutic implications in neovascular age-related macular degeneration and other vascular disorders.blindness | MAP kinase signaling | semaphorins | Akt | proangiogenic T he growth of blood vessels through angiogenesis is a delicately controlled process that involves endothelial cell (EC) activation, proliferation, migration, and maturation (1). Physiological angiogenesis is required for normal vascular development as well as vascular homeostasis during adulthood. Pathological angiogenesis, commonly induced by tissue ischemia or inflammation, underlies numerous vascular disorders, such as age-related macular degeneration (AMD), a leading cause of blindness in the elderly (2). Choroidal neovascularization (CNV), which involves abnormal growth of blood vessels in the back of the eye, is a hallmark of neovascular AMD (3). Although the pathogenic mechanisms underlying AMD are still largely unknown, vascular endothelial growth factor (VEGF) has been shown to play a causal role in the development of CNV (4). Anti-VEGF agents have demonstrated efficacy in treating CNV in neovascular AMD (5, 6) but have limited efficacy and potential side effects (7,8).Recent studies have revealed important roles for microRNAs (miRNAs) in cardiovascular diseases and other disorders (9). miRNAs are small noncoding RNAs that negatively regulate gene expression by inducing mRNA degradation or inhibiting translation through binding to the 3′ untranslated region (3′UTR) of target mRNAs (10). Often, miRNAs modulate broad collections of mRNAs encoding multiple components of complex biological pathways. Several miRNAs have been implicated in angiogenesis (11,12). A group of miRNAs has also been shown to be substantially decreased in a laser-induced CNV model (13).The miR-23∼27∼24 clusters are highly expressed in ECs (14-17). Two miR-23∼27∼24 clusters exist in the vertebrate genome: an intergenic miR-23a∼27a∼24-2 cluster and an intronic miR23b∼27b∼24-1 cluster. Members of these clusters are involved in cell cycle control, proliferation, and differentiation of various cell types (18). Here, we show that inhibition of miR-23/27 impairs angiogenesis in vitro and postnatal retinal vascular development in vivo. Moreover, silencing of miR-23/27 suppresses l...

Dietary ARG supplementation during UUO relief did not improve ERPF or GFR. However, renal damage, including fibrosis, apoptosis, and macrophage infiltration was significantly improved by ARG treatment. This suggests that increasing NO availability could be beneficial in the setting of UUO relief.

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