Platelets trigger endothelial exocytosis

Comment on Dole et al, page 2334

Dole and colleagues report that activated platelets stimulate endothelial secretion of Weibel-Palade bodies, causing leukocyte rolling in vivo. This discovery strengthens the connection between thrombosis and vascular inflammation.

Do platelets play a critical role in vascular inflammation? Activated platelets circulate in the blood of patients with a variety of inflammatory diseases, including sepsis, diabetes, and atherosclerosis. Inflammatory stimuli can activate platelets, promoting a prothrombotic state, but studies also suggest that activated platelets can modulate vascular inflammation. Activated platelets release proinflammatory cytokines and chemokines such as interleukin-1β, CD40 ligand (CD40L), and CC chemokine ligand 5 (CCL5).^1-3  However, the precise cellular mechanisms by which platelets trigger vascular inflammation are not fully understood.

In this issue of Blood, Dole and colleagues report that activated platelets stimulate endothelial exocytosis. Activated platelets infused into mice triggered endothelial secretion of Weibel-Palade bodies, externalizing P-selectin and releasing von Willebrand factor (VWF) in mouse venules. Endothelial exocytosis in turn caused leukocyte rolling along venules (see figure). This study extends prior work showing that activated platelets increased monocyte adhesion to endothelial cells in vitro,⁴  and it also fits nicely with a previous study which demonstrated that platelets triggered leukocyte adherence to endothelium overlying atherosclerotic plaques.⁵ 

Platelets thus activate endothelial exocytosis. How? Do platelets directly contact endothelial cells, triggering exocytosis? Do platelets release soluble mediators that stimulate endothelial-cell secretion? Or perhaps platelets indirectly trigger endothelial release of Weibel-Palade bodies by activating leukocytes, which in turn stimulate the endothelium. Dole and colleagues' current study supports this last concept: platelet P-selectin was necessary for endothelial activation, suggesting that platelet interaction with leukocytes through leukocyte P-selectin glycoprotein ligand 1 (PSGL-1) might be important in prompting endothelial secretion.

The current study strengthens the connection between thrombosis and vascular inflammation. Activated platelets not only release cytokines that modulate delayed endothelial expression of proinflammatory genes, but also initiate immediate vascular responses such as endothelial granule exocytosis. Further exploration of the mechanisms by which activated platelets trigger endothelial exocytosis will lead to novel therapies for inflammatory diseases such as sepsis and atherosclerosis. ▪