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Ferrata Storti Foundation
Haematologica 2019 Volume 104(8):1648-1660
Platelet Biology & its DIsorders
Platelet glycoprotein VI and C-type lectin-like receptor 2 deficiency accelerates wound healing by impairing vascular integrity in mice
Surasak Wichaiyo,1,2 Sian Lax,1 Samantha J. Montague,1 Zhi Li,3
Beata Grygielska,1 Jeremy A. Pike,4 Elizabeth J. Haining,1 Alexander Brill,1,5 Steve P. Watson,1,4,6 and Julie Rayes1
1Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; 2Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 3Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; 4Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, The Midlands, UK; 5Department of Pathophysiology, Sechenov First Moscow State Medical University, Moscow, Russia and 6Institute of Microbiology and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
ABSTRACT
Platelets promote wound healing by forming a vascular plug and by secreting growth factors and cytokines. Glycoprotein (GP)VI and C- type lectin-like receptor (CLEC)-2 signal through a (hem)-immunore- ceptor tyrosine-based activation motif, which induces platelet activation. GPVI and CLEC-2 support vascular integrity during inflammation in the skin through regulation of leukocyte migration and function, and by sealing sites of vascular damage. In this study, we investigated the role of impaired vascular integrity due to GPVI and/or CLEC-2 deficiency in wound repair using a full-thickness excisional skin wound model in mice. Transgenic mice deficient in both GPVI and CLEC-2 exhibited accelerated skin wound healing, despite a marked impairment in vascular integrity. The local and temporal bleeding in the skin led to greater plasma protein entry, including fibrinogen and clotting factors, was associated with increased fibrin gener- ation, reduction in wound neutrophils and M1 macrophages, decreased level of tumor necrosis factor (TNF)-α, and enhanced angiogenesis at day 3 after injury. Accelerated wound healing was not due to developmental defects in CLEC-2 and GPVI double-deficient mice as similar results were observed in GPVI-deficient mice treated with a podoplanin-blocking anti- body. The rate of wound healing was not altered in mice deficient in either GPVI or CLEC-2. Our results show that, contrary to defects in coagulation, bleeding following a loss of vascular integrity caused by platelet CLEC-2 and GPVI deficiency facilitates wound repair by increasing fibrin(ogen) dep- osition, reducing inflammation, and promoting angiogenesis.
Introduction
Cutaneous wound repair is a complex process, which requires a well-regulated interplay between diverse cell types and molecules.1 Four inter-related phases of wound healing have been described, namely hemostasis, inflammation, prolifera- tion, and remodeling.1 Immediately upon injury, platelets and fibrin generate a hemostatic plug to prevent excessive blood loss. Additionally, the fibrin clot forms a scaffold to promote migration of local cells surrounding the wound.2 Deficiency in clotting factors, including tissue factor (TF), factor (F)VII or FIX, results in per- sistent intra-tissue bleeding and delayed wound healing.3-5 Shortly after, neu- trophils and inflammatory macrophages (M1) are recruited to eliminate microbes and cellular debris, driving the inflammatory phase.1,6 During the proliferative phase, re-epithelialization and angiogenesis promote cell growth and wound recovery. In addition, fibroblasts infiltrate the granulation tissue to produce extra- cellular matrix proteins, and to differentiate into myofibroblasts, mediating
Correspondence:
JULIE RAYES
j.rayes@bham.ac.uk
STEVE P. WATSON
s.p.watson@bham.ac.uk
Received: October 12, 2018. Accepted: January 28, 2019. Pre-published: February 7, 2019.
doi:10.3324/haematol.2018.208363
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/8/1648
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