Endothelial PLK2 as a metabolic rheostat and therapeutic target for pathological retinal and choroidal neovascularization
TL;DR
By maintaining mitochondrial bioenergetic efficiency and mitigating oxidative stress, PLK2 sustains the high-energy demands of pathological endothelial cell activation and sprouting and represents a promising therapeutic strategy for pathological ocular angiogenesis.
Abstract
Pathological ocular neovascularization remains a leading cause of irreversible vision loss. This study investigates the role of Polo-like kinase 2 (PLK2) in coordinating the transition of endothelial cells into pathological phenotypes. Single-cell transcriptomic and clinical tissue analysis revealed that PLK2 is specifically enriched in the vascular component of human proliferative membranes and is markedly upregulated in human fibrovascular membrane tissue. PLK2 endothelial knockdown (eKD) inhibited vascular branching and tip cell filopodia formation in postnatal mice. Analysis of murine oxygen-induced retinopathy (OIR) single cell sequencing datasets identified PLK2 as a specific marker for actively sprouting tip cells and proliferative endothelial subpopulations during pathological neovascularization. PLK2 eKD or conditional knockout (eCKO) significantly attenuated pathological neovascularization in OIR. Additionally, PLK2 eKD inhibited laser-induced choroidal neovascularization (CNV) in adult mice. In vitro assays confirmed that PLK2 depletion via shRNA or CRISPR/Cas9 markedly inhibited endothelial cell proliferation, migration, and tube formation across various microvascular cells, whereas ectopic PLK2 overexpression promoted a robust pro-angiogenic phenotype. Mechanistically, PLK2 is a critical regulator of mitochondrial bioenergetics; genetic depletion led to a reduction of mitochondrial Complex I activity, decreased ATP levels, and impaired oxygen consumption, accompanied by mitochondrial membrane depolarization and the accumulation of reactive oxygen species (ROS). The anti-angiogenic effects and apoptotic induction caused by PLK2 deficiency were significantly rescued by glucose supplementation or antioxidant N-acetylcysteine (NAC) treatment. Thus, by maintaining mitochondrial bioenergetic efficiency and mitigating oxidative stress, PLK2 sustains the high-energy demands of pathological endothelial cell activation and sprouting. PLK2 represents a promising therapeutic strategy for pathological ocular angiogenesis.