Developmental regression of hyaloid vasculature is triggered by neurons.
Vascular development involves not only vascular growth, but also regression of transient or unnecessary vessels. Hyaloid vasculature is the temporary circulatory system in fetal eyes, which spontaneously degenerates when the retinal blood vessels start to grow. Failure of the hyaloid vessels to regress leads to disease in humans, persistent hyperplastic primary vitreous, which causes severe intraocular hemorrhage and impairs visual function. However, the mechanism underlying the endogenous program that mediates spontaneous regression of the hyaloid vessels is not well understood. In this study, we identify a robust switch triggering this program directed by neurons in mice. Marked up-regulation of vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) occurs in retinal neurons just after birth via distal-multipotent-mesodermal enhancer, a hemangioblast-specific enhancer of VEGFR2. Genetic deletion of neuronal VEGFR2 interrupts this program, resulting in massive hyaloid vessels that persist even during late postnatal days. This abnormality is caused by excessive VEGF proteins in the vitreous cavity as a result of impairment in the neuronal sequestration of VEGF. Collectively, our data indicate that neurons trigger transition from the fetal to the postnatal circulatory systems in the retina.
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Yusuke
Y
Yoshikawa
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Toru
0000-0002-1709-1012
T
Yamada
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Ikue
0000-0003-1665-719X
I
Tai-Nagara
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan Department of Plastic Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Keisuke
K
Okabe
Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
Yuko
Y
Kitagawa
Department of Stem Cells and Human Disease Models, Research Center for Animal Life Science, Shiga University of Medical Science, Tsukinowa-cho, Otsu 520-2192, Japan.
Masatsugu
M
Ema
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan ykubo33@a3.keio.jp.
Yoshiaki
Y
Kubota
D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D012160:Retina / Q000196:embryology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism*; D014822:Vitreous Body / Q000196:embryology
D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2