R-spondin3（RSPO3）是血管生成和血管发育的关键蛋白，RSPO3显著增强Wnt/β-catenin信号，促内皮细胞增殖、迁移及新生血管形成[1,2]。除Wnt/β-catenin信号外，Akt-mTOR的激活也对血管生成至关重要。研究表明RSPO3可激活Akt-mTOR通路[3]。但Akt-mTOR在RSPO3诱导的血管生成中的作用及相关分子机制并不明确。

课题组多年来研究证实G蛋白抑制性α亚单位1和3（Gαi1/3蛋白）是多个因子下游信号转导的关键蛋白。在生长因子刺激下，Gαi1/3和受体酪氨酸激酶（RTKs）等受体结合介导下游信号转导（Protein & Cell 2022b [4]，Science Signaling 2009[5]，Oncogene 2018, 2021^[6,7]，IJBS 2022[8]，Theranostics2018，2021a/b[9-11]等论文）。例如，前期研究发现敲减、敲除Gαi1/3后，BDNF信号传导受阻，海马神经元树突数目及单位距离的树突棘的数目均显著减少（PNAS 2018[12]，Highlight by PNAS[13]）。课题前期已证明Gαi1/3是促血管生成的关键信号蛋白。在VEGF刺激下，Gαi1/3促VEGFR2的内吞、下游Akt-mTOR转导和血管生成[11]。此外，课题组最新研究还发现磷酸烯醇式丙酮酸羧激酶1（PCK1）通过促进Gαi3表达和Akt-mTOR激活促血管生成（Science Advances 2022[14]）。

2022年8月13日，18新利体育 神经18新利备用网站 所、18新利体育 附属第二医院神经疾病中心曹聪课题组在Protein & Cell （IF = 15.3）发表了题为“Gαi1/3 mediation of Akt-mTOR activation is important for RSPO3-induced angiogenesis”文章，该研究揭示了Gαi1/3介导RSPO3诱导的Akt-mTOR通路激活、促血管新生。

研究发现在体外培养的人脐静脉内皮细胞（HUVECs）和人脑微血管内皮细胞（HCMEC/D3）中，RSOP3诱导LGR4-Gαi1/3-Gab1信号复合体的形成，介导下游Akt-mTOR的激活。RSPO3诱导的Akt-mTOR激活独立于Wnt/β-catenin信号通路。在HUVECs和HCMEC/D3细胞中，敲减Gαi1/3显著抑制RSPO3诱导的内皮细胞迁移、增殖和体外成管。而Gαi1/3过表达则增强了RSPO3诱导的体外促血管新生作用。C57小鼠内皮细胞特异性敲减Gαi1/3后显著抑制RSPO3过表达诱导的Akt-mTOR激活和小鼠视网膜血管新生；而内皮细胞特异性过表达Gαi1/3显著促进视网膜血管新生。综上，Gαi1/3介导Akt-mTOR激活对RSPO3诱导的血管生成至关重要。

原文链接：https://doi.org/10.1093/procel/pwac035

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