Genetic deletion of β1‐ and β2‐adrenergic receptors rescues the retina from hypoxia‐induced pathologic angiogenesis

Abstract

AbstractPurpose To investigate the effects of β1‐ and β2‐adrenergic receptor (AR) deletion in the vascular retinal response to hypoxia, to confirm and expand the role of β1‐ and β2‐ARs in regulating retinal angiogenesis and to get insights into the role of β3‐ARs.Methods We used wild type (WT) and β1/β2‐AR knockout (KO) mice. The retinal angiogenic response to hypoxia was studied in a mouse model of oxygen‐induced retinopathy (OIR) using real time RT‐PCR, Western blot, ELISA and immunohistochemistry.Results Our results show that β1‐ and β2‐AR deletion did not affect β3‐AR expression or norepinephrine (NE) levels. In KO mice, NE was less upregulated in response to hypoxia indicating a reduced stimulation of the β‐adrenergic system. In KO, the angiogenic response to hypoxia, including the formation of both a central avascular area and neovascular tufts, was nearly abolished while no improvements were observed in blood‐retinal barrier dysfunction typical of OIR. Unexpectedly, VEGF levels did not differ between WT and KO in spite of a recover of the angiogenic response, but a reduced activation of VEGF signaling was observed in KO, which may explain the reduced response to hypoxia. To get insights into the role of β3‐ARs, we treated OIR mice with a β3‐AR agonist, BRL37344 (2 mg/kg, s.c. injected), which resulted in an increase in VEGF levels and the formation of neovascular tufts in both WT and KO, indicating that β3‐AR stimulation may function as a proangiogenic switch.Conclusion Taken together, our results confirm the notion that β1‐ and/or β2‐ARs play a role in retinal angiogenesis and indicate that β3‐ARs may potentiate the angiogenic response in WT and sustain the angiogenic drive in KO.