Title:
Neuro-vascular crosstalk in the developing retina

 

Yoshiaki Kubota
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University

 

Abstract:
To meet tissue requirements for oxygen, blood vessels are properly distributed with an appropriate patterning customized to the function of each organ. In this process, diverse interactions between endothelial cells and other cell types contribute to the establishment of such tissue-specific vascular patternings. Our research is focusing on vascular development of the retina, a part of the central nervous system, now widely utilized as a good model to study the mechanism of angiogenesis. In retinal vascular development, a highly motile population of endothelial cells which positions the leading edge of the vasculature, namely “tip cells”, leads outgrowth of blood vessels. The most popular consensus is that VEGF-A expressed in hypoxic astrocytes which binds VEGFR2 on tip cells regulates their sprouting and migrating activity, consequently ensuring proper vascular patterning and density. Here we shed light on the role of retial neurons, which function in vascular development is surprisingly not well understood. Our data have shown that retinal neurons act as primary hypoxic sensors via activation of HIF1 and HIF2, and are necessary for coordinated retinal vascularization. Moreover, we have found that retinal neurons are actively endocytosing VEGF-A so that they orchestrate the direction and timing of retinal vascularization.

References:
1. Nakamura-Ishizu A, Kurihara T, Okuno Y, Ozawa Y, Kishi K, Goda N, Tsubota K, Okano H, Suda T and *Kubota Y. The formation of an angiogenic astrocyte template is regulated by the neuroretina in a HIF-1-dependent manner. Dev Biol 363(1): 106-14, 2012.
2. Okuno Y, Nakamura-Ishizu A, Otsu K, Suda T and *Kubota Y. Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat Med 18(8): 1208–1216, 2012.
3. Okabe K, Kobayashi S, Yamada T, Kurihara T, Tai-Nagara I, Miyamoto T, Mukouyama YS, Sato TN, Suda T, Ema M and *Kubota Y. Neurons limit angiogenesis by titrating VEGF in retina. Cell 159: 584-596, 2014.