Yoshitomi Yasuo, Ikeda Takayuki, Saito Hidehito, Yoshitake Yoshino, Ishigaki Yasuhito, Hatta Toshihisa, Kato Nobuo, Yonekura Hideto
Department of Biochemistry, Kanazawa Medical University School of Medicine, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.
Medical Research Institute, Kanazawa Medical University, 1-1 Daigaku, Uchinada, Kahoku-gun, Ishikawa 920-0293, Japan.
J Cell Sci. 2017 Mar 1;130(5):916-926. doi: 10.1242/jcs.196303. Epub 2017 Jan 17.
Blood vessels and nerve fibers are often closely arranged in parallel throughout the body. Therefore, neurovascular interactions have been suggested to be important for the development of vascular networks. However, the molecular mechanisms and genes regulating this process remain unclear. In the present study, we investigated the genes that are activated in endothelial cells (ECs) following interactions with neurons during vascular development. Microarray analyses of human primary microvascular ECs co-cultured with mouse primary dorsal root ganglion cells showed that JunB is strongly upregulated in ECs by neurovascular interactions. Furthermore, the forced expression of JunB in ECs stimulated a tip-like cell formation and angiogenesis and induced vascular endothelial growth factor A (VEGFA) and the pro-angiogenic integrin subunit ITGB3 expression. Moreover, knockdown of JunB in ECs from developing mouse limb skin considerably decreased the parallel alignments of blood vessels and nerve fibers. Taken together, the present data demonstrates for the first time that JunB plays an important role in the formation of embryonic vascular networks. These results contribute to the molecular understanding of neurovascular interactions during embryonic vascular development.
在全身各处，血管和神经纤维常常紧密平行排列。因此，有人提出神经血管相互作用对于血管网络的发育很重要。然而，调节这一过程的分子机制和基因仍不清楚。在本研究中，我们调查了血管发育过程中内皮细胞（ECs）与神经元相互作用后被激活的基因。对与小鼠初级背根神经节细胞共培养的人原代微血管内皮细胞进行微阵列分析表明，神经血管相互作用可使内皮细胞中的JunB强烈上调。此外，在内皮细胞中强制表达JunB可刺激形成尖端样细胞并促进血管生成，并诱导血管内皮生长因子A（VEGFA）和促血管生成整合素亚基ITGB3的表达。此外，敲低发育中小鼠肢体皮肤内皮细胞中的JunB会显著减少血管和神经纤维的平行排列。综上所述，目前的数据首次证明JunB在胚胎血管网络形成中起重要作用。这些结果有助于从分子层面理解胚胎血管发育过程中的神经血管相互作用。
