Antagonism of histamine H3 receptor promotes angiogenesis following focal cerebral ischemia
Antagonism of histamine H3 receptor promotes angiogenesis following focal cerebral ischemia
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DOI：
10.1038/s41401-022-00916-4
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发表时间：
2022-05
影响因子：
8.2
通讯作者：
Lishi Fan;Youchao Chen;Ru-jia Liao;Yan-yan Zhao;Xiangnan Zhang;Zhong Chen;Lei Jiang;Weiwei Hu
中科院分区：
文献类型：
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作者：
Lishi Fan;Youchao Chen;Ru-jia Liao;Yan-yan Zhao;Xiangnan Zhang;Zhong Chen;Lei Jiang;Weiwei Hu
我们的前期研究表明，H3受体拮抗剂可减少脑缺血后急性期神经细胞凋亡和脑梗死，但其作用不依赖于组胺能神经元的激活。由于增强的血管生成促进缺血性卒中后的神经发生和神经恢复，我们在此研究了H3 R的拮抗作用是否促进脑缺血后的血管生成。在小鼠中诱导光血栓性中风。我们发现，给予H3 R拮抗剂硫代哌丁胺（THIO，10 mg·kg-1·d-1，i. p.，从脑缺血后D1开始）显著改善了在D14评估的血管生成，并减轻了脑缺血后D28的神经缺陷。与野生型小鼠相比，Hrh 3 −/−小鼠在D14的缺血边界区显示出更多的血管，THIO给药并没有促进这些敲除小鼠的血管生成。小鼠中THIO促进的血管生成可通过i. c. v.注射H3 R激动剂immepip逆转，但H1和H2受体拮抗剂、组氨酸脱羧酶抑制剂α-氟甲基组氨酸或组氨酸脱羧酶基因敲除（HDC-/-）均不能逆转，这表明THIO促进的血管生成不依赖于组胺能神经元的激活。在血管内皮细胞（bEnd.3）中，THIO（10−9−10− 7 M）剂量依赖性地促进氧葡萄糖剥夺（OGD）后的细胞迁移和管形成，H3 R敲低引起类似的效应。我们进一步发现，H3 R拮抗作用减少了H3 R和膜联蛋白A2之间的相互作用，而膜联蛋白A2的敲低废除了THIO促进的血管生成后，OGD的bEnd.3细胞。膜联蛋白A2过表达的小鼠在缺血边界区显示出更多的血管，这被i. c. v.注射immepip逆转。总之，本研究表明，H3 R拮抗剂促进脑缺血后的血管生成，这是独立于组胺能神经元的激活，但与血管内皮细胞上的H3 R及其与Annexin A2的相互作用有关。因此，H3 R拮抗剂可能是改善缺血性卒中后血管生成和神经恢复的有前途的候选药物。
Our previous study showed that H3receptor antagonists reduced neuronal apoptosis and cerebral infarction in the acute stage after cerebral ischemia, but through an action independent of activation of histaminergic neurons. Because enhanced angiogenesis facilitates neurogenesis and neurological recovery after ischemic stroke, we herein investigated whether antagonism of H3R promoted angiogenesis after brain ischemia. Photothrombotic stroke was induced in mice. We showed that administration of H3R antagonist thioperamide (THIO, 10 mg·kg−1·d−1, i.p., from D1 after cerebral ischemia) significantly improved angiogenesis assessed on D14, and attenuated neurological defects on D28 after cerebral ischemia. Compared with wild-type mice,Hrh3−/−mice displayed more blood vessels in the ischemic boundary zone on D14, and THIO administration did not promote angiogenesis in these knockout mice. THIO-promoted angiogenesis in mice was reversed by i.c.v. injection of H3R agonist immepip, but not by H1and H2receptor antagonists, histidine decarboxylase inhibitor α-fluoromethylhistidine, or histidine decarboxylase gene knockout (HDC−/−), suggesting that THIO-promoted angiogenesis was independent of activation of histaminergic neurons. In vascular endothelial cells (bEnd.3), THIO (10−9−10−7M) dose-dependently facilitated cell migration and tube formation after oxygen glucose deprivation (OGD), and H3R knockdown caused similar effects. We further revealed that H3R antagonism reduced the interaction between H3R and Annexin A2, while knockdown of Annexin A2 abrogated THIO-promoted angiogenesis in bEnd.3 cells after OGD. Annexin A2-overexpressing mice displayed more blood vessels in the ischemic boundary zone, which was reversed by i.c.v. injection of immepip. In conclusion, this study demonstrates that H3R antagonism promotes angiogenesis after cerebral ischemia, which is independent of activation of histaminergic neurons, but related to the H3R on vascular endothelial cells and its interaction with Annexin A2. Thus, H3R antagonists might be promising drug candidates to improve angiogenesis and neurological recovery after ischemic stroke.