Ocular neovascularisation underlies blinding eye diseases such as retinopathy of prematurity, proliferative diabetic retinopathy, and wet age-related macular degeneration. These diseases cause irreversible vision loss, and provide a significant health and economic burden. Biologics targeting vascular endothelial growth factor (VEGF) are the major approach for treatment. However, up to 30% of patients are non-responsive to these drugs and they are associated with ocular and systemic side effects. Therefore, there is a need for small molecule ocular angiogenesis inhibitors to complement existing therapies. We examined the safety and therapeutic potential of SH-11037, a synthetic derivative of the antiangiogenic homoisoflavonoid cremastranone, in models of ocular neovascularisation. SH-11037 dose-dependently suppressed angiogenesis in the choroidal sprouting assay ex vivo and inhibited ocular developmental angiogenesis in zebrafish larvae. Additionally, intravitreal SH-11037 (1 μM) significantly reduced choroidal neovascularisation (CNV) lesion volume in the laser-induced CNV mouse model, comparable to an anti-VEGF antibody. Moreover, SH-11037 synergised with anti-VEGF treatments in vitro and in vivo. Up to 100 μM SH-11037 was not associated with signs of ocular toxicity and did not interfere with retinal function or pre-existing retinal vasculature. SH-11037 is thus a safe and effective treatment for murine ocular neovascularisation, worthy of further mechanistic and pharmacokinetic evaluation.
Retinal angiogenesis is tightly regulated to meet oxygenation and nutritional requirements. In diseases such as proliferative diabetic retinopathy and neovascular age-related macular degeneration, uncontrolled angiogenesis can lead to blindness. Our goal is to better understand the molecular processes controlling retinal angiogenesis and discover novel drugs that inhibit retinal neovascularization. Phenotype-based chemical screens were performed using the ChemBridge Diverset
These studies identified VDR agonists as significant and selective anti-angiogenics in the developing vertebrate eye and miR21 as a key downstream regulated miRNA. These targets should be further evaluated as molecular hallmarks of, and therapeutic targets for pathological ocular neovascularization.
Aberrant ocular angiogenesis can underpin vision loss in leading causesof blindness, including neovascular age-related macular degeneration and proliferative diabetic retinopathy. Current pharmacological interventions require repeated invasive administrations, may lack efficacy and are associated with poor patient compliance and tachyphylaxis. Vitamin D has de novo anti-angiogenic properties. Here, our aim was to validate the ocular anti-angiogenic activity of biologically active vitamin D, calcitriol, and selected vitamin D analogue, 22-oxacalcitriol. Calcitriol induced a significant reduction in ex vivo mouse choroidal fragment sprouting. Viability studies in a human RPE cell line suggested non-calcemic vitamin D analogues including 22-oxacalcitriol have less offtarget anti-proliferative activity compared to calcitriol and other analogues. Thereafter, the anti-angiogenic activity of 22-oxacalcitriol was demonstrated in an ex vivo mouse choroidal fragment sprouting assay. In zebrafish larvae, 22-oxacalcitriol was found to be anti-angiogenic, inducing a dose-dependent reduction in choriocapillaris development. Subcutaneously administered calcitriol failed to attenuate mouse retinal vasculature development. However, calcitriol and 22-oxacalcitriol administered intraperitoneally, significantly attenuated lesion volume in the laser-induced choroidal neovascularisation mouse model. In summary, calcitriol and 22-oxacalcitriol attenuate ex vivo and in vivo choroidal vasculature angiogenesis. Therefore, vitamin D may have potential as an interventional treatment for ophthalmic neovascular indications. InTRoduCTIonPathological neovascularisation of ocular blood vessels can promote vision loss in leading causes of blindness including neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy. Worldwide, 8.7% of blindness results from AMD. nAMD accounts for only 10% of AMD cases but greater than 80% of poor visual acuity cases [1][2][3][4]. Rapid vision loss in nAMD is driven by pathological choroidal vasculature angiogenesis. This pathological vasculature can be deficient in tight junctions, leak plasma or blood, cause scarring, project through the Bruch's membrane, cause retinal pigmented epithelium (RPE) detachment and disrupt normal perfusion of the retina [5][6][7]. Worldwide 382 million people suffer from
BackgroundPsoriatic arthritis (PsA) is characterised by an early vascular phase which is essential in perpetuating pannus growth, immune responses and disease progression. Recently, numerous studies have highlighted the emerging importance of endothelial cell metabolism in controlling angiogenesis. Herein, we propose microRNA, miR-125, modulates EC bioenergetics and orchestrates joint angiogenesis as characterised using ex-vivo and in-vitro tissue/cell assays and a novel in-vivo zebrafish model.ObjectivesTo examine the relationship between miR-125, angiogenesis and cellular metabolism in the PsA synovium.MethodsPrimary PsA synovial fibroblasts (PsA FLS) and microvascular endothelial cells (HMVEC) were transfected with anti-miR-125a. Angiogenic mechanisms were quantified using tube formation assays, invasion by Transwell Matrigel chambers, migration by wound repair and metabolic gene expression by RT-PCR. Real-time analysis of extracellular acidification rates (ECAR) and oxygen consumption rates (OCR) of anti-125 treated HMVEC was assessed using the XF-24 Flux Analyzer (Seahorse Bioscience). To determine if altered metabolism is observed ex vivo, glycolysis/oxidative phosphorylation markers (GAPDH/PKM2/GLUT1/ATP), and angiogenic factors (FactorVIII/VEGF/ANG2) were quantified by immunohistology. MiRNA levels were quantified in synovial tissue (ST) and PBMC by RT-PCR and compared to clinical marker and immunohistochemical analysis. The angiogenic effects of miR-125 were assessed in vivo using GFP-tagged zebrafish embryos treated with anti-125 morpholinos, or vitamin D3 analog, calcitrol, to monitor vascular development.ResultsAn increase in tube formation, cellular invasion and/or migration mechanisms (p<0.05) were demonstrated in anti-miR-125a transfected HMVEC and FLS supernatant. Inhibition of miR-125 significantly decreased basal, maximal and spare respiratory capacity (P<0.009) with a concurrent decrease in ATP synthesis (P<0.008). Increased glycolysis was further confirmed by the observed elevation of glycolytic genes: HK2, GSK3A, PDK1, HP6G (ns) and 3PO target and stimulator of glycolysis, PFKFB3 (P<0.05). In vivo synovial expression of miR-125 was significantly decreased in PsA versus OA synovial tissue and was associated with increased PsA macroscopic and microscopic vascularity. This was paralleled by a significant increase in the vascular expression of glycolytic markers, PKM2, GLUT1 and ATP5B in PsA compared to OA synovium. Finally, anti-125 morpholinos treated Zebrafish displayed increased vascular sprouting. In contrast, Calcitriol significantly reduced vascular development and increased the expression of miR-125, promoting miR-125 as a potential mechanism for orchestrating angiogenic development in vivo and in response to pharmaceutical agentsConclusionsOur data demonstrates decreased expression of miR-125 in PsA synovium and in-vivo models was strongly associated pro-angiogenic mechanisms. Elevated glycolysis following miR-125 inhibition may enables endothelial cells to meet the increased energy and b...
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