Anosmin-1 activates vascular endothelial growth factor receptor and its related signaling pathway for olfactory bulb angiogenesis
Anosmin-1 activates vascular endothelial growth factor receptor and its related signaling pathway for olfactory bulb angiogenesis
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DOI：
10.1038/s41598-019-57040-3
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发表时间：
2020-01-13
影响因子：
4.6
通讯作者：
Kurokawa-Seo, Misuzu
中科院分区：
文献类型：
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作者：
Matsushima, Shoko;Shimizu, Akio;Kurokawa-Seo, Misuzu
Anosmin-1是一种由ANOS1基因编码的分泌型糖蛋白，其功能丧失可导致Kallmann综合征(KS)，其特征是嗅球功能障碍所致的嗅觉障碍和性腺功能减退。然而，anosmin-1的生理功能仍有待阐明。在KS中，OB血管生成紊乱，导致其发育不良。在这项研究中，我们研究了anosmin-1在血管生成过程中的作用。鸡胚OB的血管样结构上检测到Anosmin-1，OB组织培养结果表明，Anosmin-1能促进维管芽的生长。Anosmin-1和血管内皮生长因子-A(VEGF-A)可诱导内皮细胞迁移、增殖和管状形成，两者联合作用可进一步促进内皮细胞的迁移、增殖和管状形成。我们新近发现Anosmin-1通过直接与血管内皮生长因子受体-2(VEGFR2)及其下游信号分子磷脂酶C-γ1(PLC-Gamma 1)和蛋白激酶C(PKC)结合来激活该受体。这些结果表明，Anosmin-1通过增强血管内皮生长因子功能，通过VEGFR2-PLC-Gamma 1-PKC轴在OB血管生成中发挥关键作用。
Anosmin-1 is a secreted glycoprotein encoded by the ANOS1 gene, and its loss of function causes Kallmann syndrome (KS), which is characterized by anosmia and hypogonadism due to olfactory bulb (OB) dysfunction. However, the physiological function of anosmin-1 remains to be elucidated. In KS, disordered angiogenesis is observed in OB, resulting in its hypoplasia. In this study, we examined the involvement of anosmin-1 in angiogenic processes. Anosmin-1 was detected on the vessel-like structure in OB of chick embryos, and promoted the outgrowth of vascular sprouts as shown by assays of OB tissue culture. Cell migration, proliferation, and tube formation of endothelial cells were induced by treatment with anosmin-1 as well as vascular endothelial growth factor-A (VEGF-A), and further enhanced by treatment with both of them. We newly identified that anosmin-1 activated VEGF receptor-2 (VEGFR2) by binding directly to it, and its downstream signaling molecules, phospholipase C gamma 1 (PLC gamma 1) and protein kinase C (PKC). These results suggest that anosmin-1 plays a key role in the angiogenesis of developing OB through the VEGFR2-PLC gamma 1-PKC axis by enhancing the VEGF function.