HIF signalling: The eyes have it
Introduction
Hypoxia-inducible factors (HIFs) are key regulators of the genomic response to hypoxia. They are ubiquitously expressed and play key roles in development, normal physiology and major human diseases [1]. The human eye is a complex organ interspersed with both highly vascular and avascular regions that are essential for visual function. Not surprisingly, the HIFs have been shown to have essential functions in numerous cells and tissues throughout the eye, and have also been implicated in many ophthalmologic pathologies, particularly in the retina.
Section snippets
Hypoxic signalling by the HIFs
The heterodimeric HIF transcription factors, members of the basic helix-loop-helix Per-Arnt-Sim (bHLH-PAS) family, are composed of an oxygen-regulated HIF-α subunit and a constitutively active aryl hydrocarbon receptor nuclear translocator (Arnt) subunit (also known as HIF-β) that form a functional HIF (reviewed in [1]). The HIF-α subunits are hydroxylated by three oxygen-dependent prolyl hydroxylases (PHD1-3, also known as EGLN1-3) in normoxia, leading to polyubiquitylation mediated by the von
Role of HIFs in the structure and physiology of the eye
The eye is an intricate arrangement of highly organised tissues, each comprised of multiple cell types (Fig. 1). Throughout the eye efficient oxygen delivery needs to be balanced by the consequence of vasculature obscuring the passage of light, as haemoglobin efficiently absorbs light. Consequently, some of the tissues in the eye are avascular, including the highly transparent cornea and lens, where the presence of blood vessels significantly compromises vision. Other tissues are highly
HIF/VEGF-induced retinal pathologies
The roles of HIF in responding to hypoxia, and specifically its role in promoting angiogenesis, implicate HIF in numerous ischaemic and other ophthalmologic pathologies, specifically in the retina. Retinal ischemia ensues when the retinal circulation is insufficient to meet the metabolic demands of the retina [25]. Retinal ischemia is the underlying pathophysiology responsible for a considerable proportion of the global burden of visual impairment in children and adults.
Future therapeutic opportunities
Characterising the role of the HIFs in the eye extends beyond an improved understanding of the development, function, and numerous pathologies of the eye, and may provide novel therapeutic approaches. There has been considerable interest in developing drugs to target the HIFs in ischaemic and other pathologies, both agonists and antagonists [43], [44]. The most advanced of these activate the HIFs and induce erythropoiesis by specifically targeting the PHDs, and are currently in phase III
Acknowledgements
This review was written in memory of Lorenz Poellinger, a close colleague and collaborator, who made a major contribution to this field and will be sadly missed. Supported by National Health and Medical Research Council of Australia grant 1099932 and the Ophthalmic Research Institute of Australia. The authors declare they have no conflicts of interest.
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