Late neuroprogenitors contribute to normal retinal vascular development in a Hif2a-dependent manner [RESEARCH ARTICLE]

Enrico Cristante, Sidath E. Liyanage, Robert D. Sampson, Aikaterini Kalargyrou, Giulia De Rossi, Matteo Rizzi, Justin Hoke, Joana Ribeiro, Ryea N. Maswood, Yanai Duran, Takaaki Matsuki, Nozie D. Aghaizu, Ulrich F. Luhmann, Alexander J. Smith, Robin R. Ali, and James W. B. Bainbridge

In the adult central nervous system, endothelial and neuronal cells engage in tight cross-talk as key components of the so-called neurovascular unit. Impairment of this important relationship adversely affects tissue homeostasis, as observed in neurodegenerative conditions including Alzheimer's and Parkinson's disease. In development, the influence of neuroprogenitor cells on angiogenesis is poorly understood. Here, we show in mouse that these cells interact intimately with the growing retinal vascular network, and we identify a novel regulatory mechanism of vasculature development mediated by hypoxia-inducible factor 2a (Hif2a). By Cre-lox gene excision, we show that Hif2a in retinal neuroprogenitor cells upregulates the expression of the pro-angiogenic mediators vascular endothelial growth factor and erythropoietin, whereas it locally downregulates the angiogenesis inhibitor endostatin. Importantly, absence of Hif2a in retinal neuroprogenitor cells causes a marked reduction of proliferating endothelial cells at the angiogenic front. This results in delayed retinal vascular development, fewer major retinal vessels and reduced density of the peripheral deep retinal vascular plexus. Our findings demonstrate that retinal neuroprogenitor cells are a crucial component of the developing neurovascular unit.

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