The role of heme in retinal vascular development and disease

PROJECT ABSTRACT
Retinal vascular diseases are major causes of vision loss in the United States and around the world. To better
treat these disorders, we need to understand the signaling pathways that control the growth and integrity of
retinal blood vessels. Our recent publications and preliminary data detail a novel angiogenic signaling system
centered around heme, a co-factor critical for oxygen transport, metabolism, and gene transcription. We found
that heme promotes angiogenic growth in the retina by regulating tip/stalk selection, and that reduced heme
production or import leads to reduced retinal vascularization and tissue hypoxia, similar to other retinal
vasculopathies including retinopathy of prematurity, choroidal neovascularization, and the rare but important
exudative vitreoretinopathies. Furthermore, we found that VEGF suppresses, while Norrin-bCatenin promotes,
the expression of the obligate endothelial heme importer, Flvcr2. Based on these data, we hypothesize that
heme, is involved in retinal angiogenesis and retinal vasculopathies. The Specific Aims of this proposal are to
(1) determine how heme intersects with Notch signaling to control angiogenic tip/stalk selection, (2) determine
whether induction of Flvcr2/heme signaling is sufficient and necessary to reverse the vascular defects and
downstream vision changes observed in mouse models of exudative vitreoretinopathy, and (3) characterize the
role for Flvcr2/heme in VEGF-induced angiogenic proliferation and neo-vascularization. To accomplish these
aims, we developed new tools to directly manipulate heme in cultured retinal endothelial cells and assess heme
transport and intracellular trafficking in vitro. We also generated new conditional knock-in and knock-out alleles
to manipulate endothelial heme transport in vivo. Our studies will fundamentally impact our understanding of
how endothelial heme levels are controlled, and the role of heme in retinal angiogenesis and vascular disease.

Grant Number: 5R01EY034615-03
NIH Institute/Center: NIH
Principal Investigator: Thomas Arnold