The β3 adrenoceptor in proliferative retinopathies: "Cinderella" steps out of its family shadow

In the retina, hypoxic condition leads to overgrowing leaky vessels resulting in altered metabolic supply that may cause impaired visual function. Hypoxia-inducible factor-1 (HIF-1) is a central regulator of the retinal response to hypoxia by activating the transcription of numerous target genes, including vascular endothelium growth factor, which acts as a major player in retinal angiogenesis. In the present review, oxygen urge by the retina and its oxygen sensing systems including HIF-1 are discussed in respect to the role of the beta-adrenergic receptors (β-ARs) and their pharmacologic manipulation in the vascular response to hypoxia. In the β-AR family, β1- and β2-AR have long been attracting attention because their pharmacology is intensely used for human health, while β3-AR, the third and last cloned receptor is no longer increasingly emerging as an attractive target for drug discovery. Here, β3-AR, a main character in several organs including the heart, the adipose tissue and the urinary bladder, but so far a supporting actor in the retina, has been thoroughly examined in respect to its function in retinal response to hypoxia. In particular, its oxygen dependence has been taken as a key indicator of β3-AR involvement in HIF-1-mediated responses to oxygen. Hence, the possibility of β3-AR transcription by HIF-1 has been discussed from early circumstantial evidence to the recent demonstration that β3-AR acts as a novel HIF-1 target gene by playing like a putative intermediary between oxygen levels and retinal vessel proliferation. Thus, targeting β3-AR may implement the therapeutic armamentarium against neovascular pathologies of the eye.