Fig. 5

Postulated mechanism by which anti-VCAM-CD39 protects the brain against hypoxic-ischaemic brain injury. Hypoxia after cessation of blood flow followed by reperfusion activates endothelial cells, causing them to release inflammatory mediators including ATP and cytokines TNF-α, IL-1 and IL-6. TNF-α stimulates upregulation of VCAM-1, while hypoxia directly upregulates ICAM-1. This enhances adhesion and transmigration of monocytes into the brain parenchyma. vWF released from injured endothelial cells and present in the subendothelial matrix, provides a surface for platelet adhesion and subsequent platelet aggregation ultimately resulting in clot formation. Prolonged hypoxia increases the expression of pro-inflammatory cytokines through the activation of HIF-1α in neurons and endothelial cells. These processes culminate in further endothelial activation, blood-brain barrier disruption, microglial activation and cell death. Anti-VCAM-CD39 is a bifunctional molecule that blocks endothelial transmigration by blocking VCAM-1 and delivers recombinant CD39 to the site of endothelial activation. CD39 converts proinflammatory ATP to adenosine, which activates A2B receptors to downregulate HIF-1α. Created in https://BioRender.com ATP: adenosine triphosphate; HIF-1α: hypoxia inducible factor-1; ICAM-1: Intercellular adhesion molecule-1; TNF-α: tumour necrosis factor VCAM-1: Vascular cell adhesion molecule-1; VWF; (von Willebrand factor)