Figure 2.

Neutrophil, platelet and endothelial contributions to vessel repair. In response to vessel injury, endothelial cells shed their protective glycosaminoglycan-rich layer, the endothelial glycocalyx, exposing upregulated selectins that have been mobilized to the cell surface. Activated endothelial cells secrete pro-inflammatory cytokines such as TNF-α and IL-1β that recruit circulating neutrophils and platelets to the damaged region. ROS production and dysregulated calcium homeostasis causes reductions in NO, enhanced cell contraction, vessel leakiness and the exposure of the underlying collagen-rich ECM. In some cases, neutrophils captured by upregulated selectins degranulate, releasing additional ROS and matrix-degrading MMPs. Adherent neutrophils act as secondary capture points for circulating platelets. Neutrophils undergoing NETosis capture red blood cells, platelets and fibrin, facilitating thrombosis development. Neutrophil activation results in further endothelial activation, which can lead to apoptosis of endothelial cells. In other cases, platelets anchor to upregulated vWF and P-selectin on the endothelial surface via GPIIbIIIa and PSGL-1. Adherent platelets secrete factors such as NAP-2, TGF-β and platelet extracellular vesicles (PEVs) that cause further endothelial activation, neutrophil recruitment, and promote the migration and proliferation of collagen-producing myofibroblasts. Platelets form a platelet plug at regions with severe endothelial damage, where denudation has occurred. Neutrophils infiltrate the platelet plug, causing an imbalance in the haemostatic response that shifts plug formation towards thrombotic. Activated platelets help guide crawling neutrophils through the thrombus or endothelium. Persistent or unresolved endothelial damage causes continued recruitment and activation of platelets and neutrophils, overwhelming the vessel and shifting the repair process towards thrombosis and fibrotic wound healing.