Acid sphingomyelinase deactivation post-ischemia promotes brain angiogenesis and remodeling by small extracellular vesicles
2022 | journal article. A publication with affiliation to the University of Göttingen.
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Acid sphingomyelinase deactivation post-ischemia promotes brain angiogenesis and remodeling by small extracellular vesicles
Mohamud Yusuf, A.; Hagemann, N.; Zhang, X.; Zafar, M.; Hussner, T.; Bromkamp, C. & Martiny, C. et al. (2022)
Basic Research in Cardiology, 117(1). DOI: https://doi.org/10.1007/s00395-022-00950-7
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Details
- Authors
- Mohamud Yusuf, Ayan; Hagemann, Nina; Zhang, Xiaoni; Zafar, Maria; Hussner, Tanja; Bromkamp, Carolin; Martiny, Carlotta; Tertel, Tobias; Börger, Verena; Schumacher, Fabian; Hermann, Dirk M.
- Abstract
- 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.
- Issue Date
- 2022
- Journal
- Basic Research in Cardiology
- Organization
- Klinik für Neurologie ; Universitätsmedizin Göttingen
- ISSN
- 0300-8428
- eISSN
- 1435-1803
- Language
- English
- Sponsor
- deutsche forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659
deutsche forschungsgemeinschaft 501100001659
bundesministerium für bildung und forschung http://dx.doi.org/10.13039/501100002347
ministerium für kultur und wissenschaft des landes nordrhein-westfalen 501100014690
europäische union
Universitätsklinikum Essen 100017590