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Sandra Suarez, Joshua Barnett, John Penn; The Role of Endoglin in Retinal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5599.
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© ARVO (1962-2015); The Authors (2016-present)
Anti-VEGF therapies are the current standard of care for treating diseases characterized by retinal or choroidal neovascularization (NV), such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). However, undesirable side effects and limited efficacy in certain subsets of patients have given rise to the exploration of non-VEGF-mediated therapies. Soluble endoglin (CD105) has been shown to be upregulated in the vasculature of certain tumors. The present study investigates the roles of hypoxia and VEGF on endoglin (CD105) expression in human retinal microvascular endothelial cells (HRMEC), and assesses the efficacy afforded by an endoglin antagonist in a rat model of oxygen-induced retinopathy (OIR).
HRMEC were exposed to hypoxia (4.6%CO2, 0.3%O2) or VEGF (25ng/mL) in culture medium containing 2% FBS, and endoglin expression was assessed by ELISA. Rats were exposed to OIR conditions, and endoglin expression was characterized by western blot analysis and immunohistochemistry (IHC). The effect of a dose range of blocking CD105 antibody on NV in OIR rats was determined by measurement of neovascular area (µm2).
Hypoxia led to a significant increase in endoglin expression in HRMEC (p<0.001). Culture medium collected from HRMEC treated with VEGF also showed an increase in endoglin expression (p<0.01), but VEGF failed to elicit the same response in HRMEC lysates (p=0.35). Compared to controls, the retinas of OIR rats demonstrated increased early endoglin upregulation as determined by both western blot analysis and IHC. Increasing concentrations of anti-endoglin led to dose-dependent reductions in neovascular area in OIR-exposed rats: 18% (0.01 mg/mL), 31% (0.1 mg/mL; p<0.05), and 47% (1.0 mg/mL; p<0.05).
Preliminary investigation has confirmed a role for endoglin in the angiogenic endothelial cell response, and blocking this protein inhibits retinal NV in a clinically-relevant animal model. Thus, these findings suggest that endoglin may provide an efficacious and VEGF-independent strategy for disease conditions characterized by retinal or choroidal NV.
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