血管生成
酸性鞘磷脂酶
鞘磷脂磷酸二酯酶
地昔帕明
药理学
鞘磷脂
阿米替林
细胞生物学
缺血
内皮干细胞
化学
生物
生物化学
内分泌学
内科学
医学
癌症研究
抗抑郁药
海马体
体外
膜
作者
Ayan Mohamud Yusuf,Nina Hagemann,Xiaoni Zhang,Maria Zafar,Tanja Hussner,Carolin Bromkamp,Carlotta Martiny,Tobias Tertel,Verena Börger,Fabian Schumacher,Fiorella A. Solari,Mike Hasenberg,Christoph Kleinschnitz,Thorsten R. Doeppner,Burkhard Kleuser,Albert Sickmann,Matthias Gunzer,Bernd Giebel,Richard Kolesnick,Erich Gulbins,Dirk M. Hermann
标识
DOI:10.1007/s00395-022-00950-7
摘要
Abstract Antidepressants have been reported to enhance stroke recovery independent of the presence of depressive symptoms. They have recently been proposed to exert their mood-stabilizing actions by inhibition of acid sphingomyelinase (ASM), which catalyzes the hydrolysis of sphingomyelin to ceramide. Their restorative action post-ischemia/reperfusion (I/R) still had to be defined. Mice subjected to middle cerebral artery occlusion or cerebral microvascular endothelial cells exposed to oxygen–glucose deprivation were treated with vehicle or with the chemically and pharmacologically distinct antidepressants amitriptyline, fluoxetine or desipramine. Brain ASM activity significantly increased post-I/R, in line with elevated ceramide levels in microvessels. ASM inhibition by amitriptyline reduced ceramide levels, and increased microvascular length and branching point density in wildtype, but not sphingomyelinase phosphodiesterase-1 ([ Smpd1 ] −/− ) (i.e., ASM-deficient) mice, as assessed by 3D light sheet microscopy. In cell culture, amitriptyline, fluoxetine, and desipramine increased endothelial tube formation, migration, VEGFR2 abundance and VEGF release. This effect was abolished by Smpd1 knockdown. Mechanistically, the promotion of angiogenesis by ASM inhibitors was mediated by small extracellular vesicles (sEVs) released from endothelial cells, which exhibited enhanced uptake in target cells. Proteomic analysis of sEVs revealed that ASM deactivation differentially regulated proteins implicated in protein export, focal adhesion, and extracellular matrix interaction. In vivo, the increased angiogenesis was accompanied by a profound brain remodeling response with increased blood–brain barrier integrity, reduced leukocyte infiltrates and increased neuronal survival. Antidepressive drugs potently boost angiogenesis in an ASM-dependent way. The release of sEVs by ASM inhibitors disclosed an elegant target, via which brain remodeling post-I/R can be amplified.
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