Dasatinib induces loss of vascular integrity and promotes cutaneous wound repair in mice.

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.

• Authors: Surasak Wichaiyo, Saovaros Svasti, Wasu Supharattanasitthi, Noppawan Phumala Morales
• Journal: Journal of thrombosis and haemostasis : JTH (J Thromb Haemost) Vol. 19 Issue 12 Pg. 3154-3167 (12 2021) ISSN: 1538-7836 [Electronic] England
• PMID: 34402195 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 International Society on Thrombosis and Haemostasis.

Chemical References

• Lectins, C-Type
• Platelet Membrane Glycoproteins
• Protein-Tyrosine Kinases
• Dasatinib

Topics

• Animals
• Blood Platelets
• Dasatinib (therapeutic use)
• Lectins, C-Type
• Mice
• Platelet Activation
• Platelet Membrane Glycoproteins
• Protein-Tyrosine Kinases
• Skin
• Wound Healing (drug effects)