Abstract
Purpose :
Vascular endothelial growth factor A (VEGF-A) signaling through VEGF receptor 1 (VEGFR1) and VEGFR2 regulates both physiological and pathological angiogenesis. We have reported that genetic deletion and pharmalogical inhibition of the VEGFR1 ligand, PlGF, reduced vasoobliteration and neovascularization in OIR [IOVS 2009; 50:E-Abstract 2943; IOVS 2010; 51:E-Abstract 4486, IOVS 2011; 52:E-Abstract 6064; IOVS 2013; 54:E-Abstract 4654]. In this study, we administered a VEGFR1 blocking antibody, αVEGFR1 to evaluate the effects of selective blockade of activity in the murine model of Retinal Vascular Development (RVD) and Oxygen Induced Retinopathy (OIR).
Methods :
RVD Studies: Study 1: Wild type (WT) C57Bl6 mice were intravitreally (IVT) injected with 5µg Fc (control) and αVEGFR1 and DC101, a VEGFR2 antibody at P4 and collected at P6;
Study 2: WT mice were systemically (IP) injected with 25mg/kg Fc, αVEGFR1 and DC101 at P2 and collected at P5;
OIR Studies: Study 1: WT mice were placed in a hyperoxic environment (75% O2) at P6 and returned to room air at P11. Pups were injected IVT with 5µg Fc, αVEGFR1, or DC101 at P13 and collected at P16;
Study 2: OIR WT mice were injected IP with 25mg/kg Fc, αVEGFR1, or DC101 at P12 and collected at P16;
Study 3: OIR WT mice were injected IP with 12.5mg/kg Fc, αVEGFR1, or DC101 at P12 and collected at P16;
Results :
In the RVD model, both αVEGFR1 and DC101 exhibit inhibitory effects, decreasing vascular outgrowth with IVT by -31% (n=6 eyes/group, p < 0.005) and -18% (n=6, p <0.001) and with IP by -21% (n=6, p <0.05) and -14% (n=6, p <0.01) compared to Fc. In the OIR model at P16, abnormal neovascularizations were reduced in IVT treated mice with αVEGFR1 (-60%, n=6, p <0.0005) and increased with DC101 (+50%, n=6, p <0.0005) relative to controls. In the OIR model, neovascularizations also reduced in IP treated mice with αVEGFR1 (-80%, n=6, p <0.0005 @25mg/kg and -60%, n=6, p <0.0005 @12.5mg/kg) and increased with DC101 (+46%, n=6, p <0.0005 at 25mg/kg and +24%, p < [email protected]/kg) relative to controls.
Conclusions :
This study demonstrates that selective pharmacological neutralization of VEGFR1 is effective in ameliorating pathological neovascularization in OIR not VEGFR2. Thus, this study further supports the hypothesis that blockade of VEGFR1 can be an important approach in the inhibition of retinal pathological angiogenesis.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.