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Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development.

ABSTRACT: Molecular oxygen is essential for the development, growth and survival of multicellular organisms. Hypoxic microenvironments and oxygen gradients are generated physiologically during embryogenesis and organogenesis. In the eye, oxygen plays a crucial role in both physiological vascular development and common blinding diseases. The retinal pigment epithelium (RPE) is a monolayer of cells essential for normal ocular development and in the mature retina provides support for overlying photoreceptors and their vascular supply. Hypoxia at the level of the RPE is closely implicated in pathogenesis of age-related macular degeneration. Adaptive tissue responses to hypoxia are orchestrated by sophisticated oxygen sensing mechanisms. In particular, the von Hippel-Lindau tumour suppressor protein (pVhl) controls hypoxia-inducible transcription factor (HIF)-mediated adaptation. However, the role of Vhl/Hif1a in the RPE in the development of the eye and its vasculature is unknown. In this study we explored the function of Vhl and Hif1a in the developing RPE using a tissue-specific conditional-knockout approach. We found that deletion of Vhl in the RPE results in RPE apoptosis, aniridia and microphthalmia. Increased levels of Hif1a, Hif2a, Epo and Vegf are associated with a highly disorganised retinal vasculature, chorioretinal anastomoses and the persistence of embryonic vascular structures into adulthood. Additional inactivation of Hif1a in the RPE rescues the RPE morphology, aniridia, microphthalmia and anterior vasoproliferation, but does not rescue retinal vasoproliferation. These data demonstrate that Vhl-dependent regulation of Hif1a in the RPE is essential for normal RPE and iris development, ocular growth and vascular development in the anterior chamber, whereas Vhl-dependent regulation of other downstream pathways is crucial for normal development and maintenance of the retinal vasculature.

SUBMITTER: Lange CA

PROVIDER: S-EPMC3367444 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

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Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development.

Lange Clemens A K CA Luhmann Ulrich F O UF Mowat Freya M FM Georgiadis Anastasios A West Emma L EL Abrahams Sabu S Sayed Haroon H Powner Michael B MB Fruttiger Marcus M Smith Alexander J AJ Sowden Jane C JC Maxwell Patrick H PH Ali Robin R RR Bainbridge James W B JW

Development (Cambridge, England) 20120523 13

Molecular oxygen is essential for the development, growth and survival of multicellular organisms. Hypoxic microenvironments and oxygen gradients are generated physiologically during embryogenesis and organogenesis. In the eye, oxygen plays a crucial role in both physiological vascular development and common blinding diseases. The retinal pigment epithelium (RPE) is a monolayer of cells essential for normal ocular development and in the mature retina provides support for overlying photoreceptors ...[more]

PMID: 22627278

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Project description:ObjectiveCharacterization of the structural and functional progression of ocular von Hippel-Lindau (VHL) disease and analysis of patient factors influencing disease progression.DesignRetrospective analysis of a case series from a longitudinal, observational study.ParticipantsTwo hundred forty-nine participants with clinically defined systemic VHL disease and more than 2 years of ophthalmic follow-up.MethodsStandardized scoring of ocular phenotype and systemic characteristics was performed at each study visit and was analyzed longitudinally to determine progression of ocular VHL disease.Main outcome measuresMeasures evaluated include: visual acuity, features of ocular VHL disease (presence, location, number, and extent of retinal capillary hemangioblastomas [RCHs]), germline mutation in the VHL gene, demographics (age, gender, age at onset of ocular disease), and patient characteristics (smoking status, body mass index).ResultsMost participants demonstrated relative anatomic and functional stability in ocular VHL disease status over a mean follow-up of 8.2 ± 4.0 years. Approximately three quarters (73%) of participants without ocular VHL disease at baseline remained disease free at the end of follow-up. Among eyes with ocular VHL disease at baseline, 88% did not demonstrate RCHs in a new retinal location, 70% remained stable in RCH number, and 79% remained stable in the extent of RCH involvement. Mean visual acuity for all study eyes (n = 498) decreased by 5.1 ± 0.6 letters across follow-up, with 16.1% of study eyes decreasing by more than 10 letters in visual acuity. Among eyes affected at baseline, greater vision loss was associated with the presence of juxtapapillary RCHs, development of RCH in a new location, and increase in peripheral RCH number and extent. Younger baseline age, younger age at onset of ocular VHL disease, involvement of the fellow eye with ocular VHL disease, and missense or protein-truncating germline mutations were associated significantly with increased anatomic involvement and functional deterioration.ConclusionsPatients with ocular VHL disease maintain relative anatomic and functional stability, with only a minority demonstrating marked anatomic progression and vision loss. Systemic and ocular risk factors for anatomic progression and vision loss can help practitioners identify patients with a higher risk profile for counseling, closer follow-up, and proactive treatment.Financial disclosure(s)The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Dataset Information

Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development.

Publications

Von Hippel-Lindau protein in the RPE is essential for normal ocular growth and vascular development.

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