HIF signalling: The eyes have it

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Abstract

The hypoxia inducible factors (HIFs) promote changes in gene expression in response to hypoxia, and mediate key physiological responses such as angiogenesis. They play important roles in development and normal physiology, as well as in ischaemic and other pathologies. The human eye is a complex organ, with tight regulation of vascularisation and oxygen delivery, with the highly specialised retina containing both highly vascularised and avascular regions. This review, written to honour the significant contribution of Lorenz Poellinger to this field, covers the role of the HIFs in normal development of the eye, specifically the vasculature, as well as their roles in numerous retinal pathologies, including ischaemic retinopathies, and age-related macular degeneration (AMD). The characterisation of the HIFs in the eye has improved our understanding of the development, function, and numerous pathologies of the eye, and should inform future therapeutic approaches.

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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