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Eunice Cheung, Ivan B Lobov, George D Yancopoulos, Stanley J Wiegand; Inhibiting Platelet Derived Growth Factor Receptor β (PDGFRβ) reduces pericytes coverage and effects vessel morphology and growth in developing retinal vessels in pups but not mature vessels in adult mice. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4361.
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PDGF-B/PDGFRβ signaling plays a well-established role during normal vascular development, and as well as physiological and pathological angiogenesis [Andrae et. al., Genes Dev. 2008, 10: 1276-312]. In these studies, we used a neutralizing antibody against PDGFRβ (αPDGFRβ) to evaluate the systemic dose response effects on pericyte coverage and the systemic effects on vascular outgrowth and density. In addition, we also evaluated the effects of inhibition of PDGFRβ signaling on pericyte recruitment on developing blood vessels and on adult mature blood vessels.
C57Bl/6 pups were given a subcutaneous (SC) injection of αPDGFRβ (50mg/kg, 25mg/kg, 12.5mg/kg, or 6.25mg/kg) at P2 and the effect on the pericyte coverage was assessed at P5 using αNG2 (Millipore), a pericyte marker. Fc (50mg/kg) was used as a control (Study 1). P2 pups were injected SC with 25mg/kg αPDGFRβ or control. Retinas were collected at P5 stained with GS Lectin I (Vector Labs) (Study 2). Left eyes of pups were injected intravitreally (IVT) with 5μg of αPDGFRβ or control at P4. Left eyes of adult mice were injected with IVT with 5μg or 10μg of αPDGFRβ or control. Eyes were collected 48hrs later and stained with αNG2 and GS Lectin I (Study 3).
All doses of αPDGFRβ ≥ 12.5 mg/kg inhibited blood vessel pericyte coverage. At a 25mg/kg dose, αPDGFRβ decreased retinal vascularized areas and vessel lengths compared to controls. A single IVT αPDGFRβ administration almost completely depleted mural cells from the developing retinal vessels, and produced marked effects on retinal vascular differentiation and morphology. In adult mice, αPDGFRβ produced no evidence of any pericytes loss or any vascular morphological changes.
These studies demonstrate that selective pharmacological neutralization of PDGFRβ is effective in promoting pericyte depletion and contributes to changes in vascular morphology and growth in developing retinal neovessels. In contrast, the inhibition of PDGFRβ does not appear to have any effect on mature pericytes and vessels in the established vasculature in the adult mouse retina.
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