Late neuroprogenitors contribute to normal retinal vascular development in a Hif2a-dependent manner

Abstract

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 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 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.

Roles of HIFs and VEGF in angiogenesis in the retina and brain

“…We also present a genetic analysis of the different roles of Hif-1α and Hif-2α in Müller glia versus neurons in the context of normal versus Norrin-deficient retinal vascular development. These results support and extend those of previous studies (16,17,22,24) and demonstrate that (a) the hypoxia response of retinal neurons is mediated by HIF-1α and is required for development recombination of all 4 alleles is required to generate a defect in retinal vascular development. Although the cortical thinning in Vegf-and Hif-α-KO mice is most simply explained as a secondary effect of hypovascularization, a reduction in glia-derived VEGF could also have a direct effect on the development and survival of cortical neurons (33).…”

“…Distinct roles for HIF-1α and HIF-2α in the development of intraretinal capillaries. HIF-1α and HIF-2α play essential roles in the development of inner plexiform layer (IPL) and outer plexiform layer (OPL) capillaries, respectively (11,16,17). To confirm and extend these observations, we began by quantitatively assessing the vascular phenotypes associated with loss of Hif-1α, Hif-2α, or both Hif-1α and Hif-2α in retinal neurons and Müller glia ( Figure 1, A-C).…”

Neuronal deficiency of hypoxia‐inducible factor 2α increases hypoxic‐ischemic brain injury in neonatal mice

“…VEGF‐A, another HIF‐1α target implicated in angiogenesis and cerebral microvasculature reconstruction during brain recovery, is also more significantly regulated by HIF‐2α in human umbilical vein endothelial cells (Downes et al., 2018) and primary cortical neurons (Ralph et al., 2004). This is in line with the function of HIF‐2α in neurovascular development (Cristante et al., 2018). Chromatin immunoprecipitation (ChIP) studies using cancer (Mole et al., 2009; Smythies et al., 2019) or endothelial cell lines (Bartoszewski et al., 2019) revealed that the two HIFα isoforms have differential but complementary transcriptional regulation (Downes et al., 2018).…”

Retinal ganglion cell interactions shape the developing mammalian visual system

“…Visual deprivation (particularly during the fetal period in mice) or deleting melanopsin ( Opn4 knockout mice) leads to persistence of the hyaloid artery and overgrowth of the retinal vascular plexus. Elevated retinal neuron numbers in dark-reared or Opn4 knockout mice leads to a more hypoxic retina, increased retinal Vegfa production and feedback to the vascular compartment that expresses VEGF receptors (Vegfr2) ( Rao et al, 2013 ; Cristante et al, 2018 ). In addition, RGCs that express another opsin, Opn5 , indirectly regulate vascular development ( Nguyen et al, 2019 ).…”