Abstract
Ocular angiogenic diseases, characterized by abnormal blood vessel formation in the eye, are the leading cause of blindness. Although Anti-VEGF therapy is the first-line treatment in the market, a substantial number of patients are refractory to it or may develop resistance over time. As uncontrolled proliferation of vascular endothelial cells is one of the characteristic features of pathological neovascularization, we aimed to investigate the role of the class I histone deacetylase (HDAC) inhibitor Largazole, a cyclodepsipeptide from a marine cyanobacterium, in ocular angiogenesis. Our study showed that Largazole strongly inhibits retinal vascular endothelial cell viability, proliferation, and the ability to form tube-like structures. Largazole strongly inhibits the vessel outgrowth from choroidal explants in choroid sprouting assay while it does not affect the quiescent choroidal vasculature. Largazole also inhibits vessel outgrowth from metatarsal bones in metatarsal sprouting assay without affecting pericytes coverage. We further demonstrated a cooperative effect between Largazole and an approved anti-VEGF drug, Alflibercept. Mechanistically, Largazole strongly inhibits the expression of VEGFR2 and leads to an increased expression of cell cycle inhibitor, p21. Taken together, our study provides compelling evidence on the anti-angiogenic role of Largazole that exerts its function through mediating different signaling pathways.
Highlights
Abnormal blood vessel formation in the eye is a characteristic feature of many blinding eye diseases, such as neovascular age-related macular degeneration and proliferative diabetic retinopathy (PDR) [1]. nAMD is caused by vascular malformations in the choroidal vasculature, which becomes hyperproliferative and penetrates the retinal pigmented epithelium into the subretinal space, especially in the macular region of the retina [2]. nAMD is the leading cause of vision loss in adults aged over 65 years [3]
As angiogenesis is a highly context-dependent process [28], we investigated the impact of Largazole on human retinal endothelial cells (HRECs) activation
To further understand the effect of Largazole on HREC proliferation, vehicle- and Largazole-treated HRECs were subjected to immunofluorescence staining with an antibody specific to Ki67, a cell proliferation marker
Summary
Abnormal blood vessel formation in the eye is a characteristic feature of many blinding eye diseases, such as neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR) [1]. nAMD is caused by vascular malformations in the choroidal vasculature, which becomes hyperproliferative and penetrates the retinal pigmented epithelium into the subretinal space, especially in the macular region of the retina [2]. nAMD is the leading cause of vision loss in adults aged over 65 years [3]. Abnormal blood vessel formation in the eye is a characteristic feature of many blinding eye diseases, such as neovascular age-related macular degeneration (nAMD) and proliferative diabetic retinopathy (PDR) [1]. NAMD is caused by vascular malformations in the choroidal vasculature, which becomes hyperproliferative and penetrates the retinal pigmented epithelium into the subretinal space, especially in the macular region of the retina [2]. NAMD is the leading cause of vision loss in adults aged over 65 years [3]. PDR, on the other hand, is caused by excessive neovascularization in the light-sensing neuroretina, which may invade the vitreous body to cause severe vision impairment and even blindness. PDR is the most common cause of vision impairment in working-age adults, which has devastating personal and socioeconomic consequences [5,6].
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