Yoshikawa Yusuke, Yamada Toru, Tai-Nagara Ikue, Okabe Keisuke, Kitagawa Yuko, Ema Masatsugu, Kubota Yoshiaki
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.
Department of Vascular Biology, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-8582, Japan.
J Exp Med. 2016 Jun 27;213(7):1175-83. doi: 10.1084/jem.20151966. Epub 2016 Jun 20.
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.
血管发育不仅涉及血管生长，还涉及短暂或不必要血管的消退。玻璃体血管系统是胎儿眼睛中的临时循环系统，当视网膜血管开始生长时，它会自发退化。玻璃体血管未能消退会导致人类疾病，即持续性增生性原发性玻璃体，这会导致严重的眼内出血并损害视觉功能。然而，介导玻璃体血管自发消退的内源性程序的潜在机制尚未完全了解。在这项研究中，我们在小鼠中确定了一种由神经元引导的强大开关，触发了这个程序。出生后不久，血管内皮生长因子（VEGF）受体2（VEGFR2）通过远端多能中胚层增强子（VEGFR2的成血管细胞特异性增强子）在视网膜神经元中显著上调。神经元VEGFR2的基因缺失会中断这个程序，导致大量玻璃体血管即使在出生后晚期仍持续存在。这种异常是由于玻璃体腔内VEGF蛋白过多所致，这是由于神经元对VEGF的隔离受损。总的来说，我们的数据表明神经元触发了视网膜中从胎儿循环系统到出生后循环系统的转变。
