Abstract
Wet age-related macular degeneration, which is characterized by choroidal neovascularization (CNV) and induces obvious vision loss. Vascular endothelial growth factor (VEGF) family member VEGF-A (also named as VEGF) and its receptor VEGFR2 contribute to the pathogenesis of CNV. Choroidal endothelial cells (CECs) secret C–C motif chemokine ligand 2 (CCL2), which attracts macrophages to CNV lesion and promotes macrophage M1 polarization. Accordingly, infiltrating macrophages secret inflammatory cytokines to promote CNV. In vivo, intravitreal injection of fruquintinib (HMPL-013), an antitumor neovascularization drug, alleviated mouse CNV formation without obvious ocular toxicity. Meanwhile, HMPL-013 inhibited VEGF/VEGFR2 binding in CECs and macrophages, as well as macrophage M1 polarization. In vitro, noncontact coculture of human choroidal vascular endothelial cells (HCVECs) and macrophages under hypoxia conditions was established. HMPL-013 downregulated VEGF/VEGFR2/phosphoinositide-3-kinase/protein kinase B (AKT)/nuclear factor kappa B pathway and CCL2 secretion in HCVECs, as well as VEGF/VEGFR2-induced macrophage M1 polarization under hypoxia condition. In addition, HMPL-013 inhibited HCEVC derived CCL2-induced macrophage migration and M1 polarization, along with macrophage M1 polarization-induced HCVECs proliferation, migration, and tube formation. Altogether, HMPL-013 alleviated CNV formation might via breaking detrimental cross talk between CECs and macrophages.
Highlights
Age-related macular degeneration (AMD), a leading cause of incurable vision loss in the elder people and accounting for 8.7% of all cases of blindness in the developed nations[1], is categorized into dry and wet types.Dry AMD is featured by multiple drusen deposits and rarely impacts vision, developing to geographic atrophy and to wet AMD, which is characterized by choroidal neovascularization (CNV) and induces obvious vision loss
The concentration–time profiles of HMPL-013 in the mouse retina–retinal pigment epithelium (RPE)–choroid complex tissues after [14C] HMPL-013 intravitreal injection showed that HMPL-013 reached its peak concentration at 4 h (13649.21 ng/ml ± 1024.80 ng/ml) and the high concentration sustained until 20 h (Fig. 1b)
The leakage score analysis further showed that the percentage of 0 and 1 scores increased, while the percentages of 2a and 2b scores decreased, in the HMPL-013 and RBZ groups compared to the CNV 7 d group (Fig. 1d)
Summary
Age-related macular degeneration (AMD), a leading cause of incurable vision loss in the elder people and accounting for 8.7% of all cases of blindness in the developed nations[1], is categorized into dry and wet types. Dry AMD is featured by multiple drusen deposits and rarely impacts vision, developing to geographic atrophy and to wet AMD, which is characterized by choroidal neovascularization (CNV) and induces obvious vision loss. Vascular endothelial growth factor (VEGF) family members, containing VEGF-A ( named as VEGF), VEGF-B, VEGF, VEGF-D, VEGF-E, and placental growth factor (PGF), promote CNV via binding to their respective receptors vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR2, and VEGFR3. Intravitreal injection of anti-VEGF reagents is deemed to be the optimal treatment for CNV. Any improvement is accompanied by long-term monthly intravitreal injections and ocular complications, such as endoophthalmitis[2].
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