Abstract
Background: Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Different ECM proteins are known to initiate platelet adhesion and activation. In atherosclerotic mice, the small, leucine-rich proteoglycan biglycan is important for the regulation of thrombin activity via heparin cofactor II. However, nothing is known about the role of biglycan for hemostasis and thrombosis under nonatherosclerotic conditions. Methods: The role of biglycan for platelet adhesion and thrombus formation was investigated using a recombinant protein and biglycan knockout mice. Results: The present study identified biglycan as important ECM protein for the adhesion and activation of platelets, and the formation of three-dimensional thrombi under flow conditions. Platelet adhesion to immobilized biglycan induces the reorganization of the platelet cytoskeleton. Mechanistically, biglycan binds and activates the major collagen receptor glycoprotein (GP)VI, because reduced platelet adhesion to recombinant biglycan was observed when GPVI was blocked and enhanced tyrosine phosphorylation in a GPVI-dependent manner was observed when platelets were stimulated with biglycan. In vivo, the deficiency of biglycan resulted in reduced platelet adhesion to the injured carotid artery and prolonged bleeding times. Conclusions: Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury.
Highlights
Platelets are small anucleate cells of the hematopoietic system and play a major role in hemostasis
We have shown that genetic deletion of the small proteoglycan biglycan interferes with hemostasis and protects against arterial thrombosis induced by reduced platelet binding to the injured vessel
Platelets are capable to bind to immobilized and soluble biglycan to increase GPVI signaling via tyrosine phosphorylation, leading to platelet degranulation and β3-integrin activation important for platelet adhesion and thrombus formation
Summary
Platelets are small anucleate cells of the hematopoietic system and play a major role in hemostasis. Injury of the endothelium induces the exposure of the extracellular matrix (ECM) that serves as substrate to initiate the activation, adhesion, and aggregation of circulating platelets [3,4]. The major components of the vascular matrix are fibrillar collagens (type I and III) known to capture circulating von Willebrand factor (VWF) to mediate adhesion and activation of platelets through GPVI and integrin α2β1 [4]. Vascular injury induces the exposure of subendothelial extracellular matrix (ECM) important to serve as substrate for platelets to adhere to the injured vessel wall to avoid massive blood loss. Conclusions: Loss of biglycan in the vessel wall of mice but not in platelets led to reduced platelet adhesion at the injured carotid artery and prolonged bleeding times, suggesting a crucial role for biglycan as ECM protein that binds and activates platelets via GPVI upon vessel injury
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