Publication: Dasatinib induces loss of vascular integrity and promotes cutaneous wound repair in mice
Issued Date
2021-12-01
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ISSN
15387836
15387933
15387933
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2-s2.0-85113680041
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Mahidol University
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SCOPUS
Bibliographic Citation
Journal of Thrombosis and Haemostasis. Vol.19, No.12 (2021), 3154-3167
Suggested Citation
Surasak Wichaiyo, Saovaros Svasti, Wasu Supharattanasitthi, Noppawan Phumala Morales Dasatinib induces loss of vascular integrity and promotes cutaneous wound repair in mice. Journal of Thrombosis and Haemostasis. Vol.19, No.12 (2021), 3154-3167. doi:10.1111/jth.15499 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/77544
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Title
Dasatinib induces loss of vascular integrity and promotes cutaneous wound repair in mice
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Abstract
Background: Inflammatory bleeding due to depletion of platelet glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) has been proposed as a potential novel mechanism to promote skin wound healing. Dasatinib inhibits a broad range of tyrosine kinases, including Src and Syk, the signaling molecules downstream of GPVI and CLEC-2. Objectives: To investigate whether dasatinib affects skin wound healing. Methods: A single (4-mm diameter) full-thickness excisional skin wound was generated in mice. Dasatinib (5 or 10 mg/kg) or dimethyl sulfoxide (DMSO) vehicle was intraperitoneally injected daily during the first 4 days. The wound was monitored over 9 days post injury. Results: Dasatinib induced loss of vascular integrity during the inflammatory phase of wound repair (day 1 to day 3 post injury), which was associated with the inhibition of platelet function stimulated by collagen and rhodocytin, the ligands for GPVI and CLEC-2, respectively. Dasatinib-treated mice, particularly at 5 mg/kg, exhibited accelerated wound closure compared to DMSO-treated controls. Transient bleeding into the wound during the inflammatory phase in dasatinib-treated mice allowed for extravasation of fibrinogen. The increased deposition of fibrinogen and fibrin in the wound on day 3 post injury was associated with the augmented progression of re-epithelialization and angiogenesis, attenuated infiltration of neutrophils and macrophages, and decreased levels of tumor necrosis factor-α (TNF-α). Conclusions: Our data show that dasatinib promotes skin wound healing, and the mechanisms include blocking GPVI- and CLEC-2-mediated platelet activation, leading to self-limited inflammatory bleeding and fibrinogen/fibrin deposition, in association with reduced inflammation, increased re-epithelialization, and enhanced angiogenesis.