Abstract
Endothelial cells serve as gatekeepers of vascular hemostasis and local inflammatory reactions. They can rapidly respond to changes in the environment, caused, for example, by blood vessel injury, tissue damage or infection, by secreting in a strictly regulated manner factors regulating these processes. These factors include adhesion receptors for circulating leukocytes and platelets, P-selectin and von-Willebrand factor (VWF) that are stored in specialized secretory granules of endothelial cells, the Weibel-Palade bodies (WPB). Acute exposure of these adhesion molecules converts the endothelial cell surface from an anti-adhesive state enabling unrestricted flow of circulating blood cells to an adhesive one capable of capturing leukocytes (through P-selectin) and platelets (through VWF). While these are important (patho)physiological responses, compromised or dysregulated WPB secretion can cause pathologies such as excessive bleeding or vascular occlusion. Several factors are involved in regulating the exocytosis of WPB and thus represent potential targets for therapeutic interventions in these pathologies. Among them, the annexin A2 (AnxA2)-S100A10 complex has been shown to participate in the tethering/docking of secretion-competent WPB at the plasma membrane, and interference with AnxA2/S100A10 expression or complex formation significantly reduces acute WPB exocytosis and VWF release. Thus, developing specific means to efficiently block AnxA2-S100A10 complex formation in endothelial cells could lead to novel avenues towards interfering with acute vascular thrombosis.
Highlights
Endothelial cells serve as gatekeepers of vascular hemostasis and local inflammatory reactions
These factors include adhesion receptors for circulating leukocytes and platelets, P-selectin and von-Willebrand factor (VWF) that are stored in specialized secretory granules of endothelial cells, the Weibel-Palade bodies (WPB)
This transition critically depends on the acute and tightly regulated exposure of adhesion molecules, most notably von-Willebrand factor (VWF) and P-selectin, which serve as receptors for platelets and leukocytes, respectively, and are stored in large secretory granules of endothelial cells, the Weibel-Palade bodies (WPB) discovered in electron microscopy sections of arterial endothelia by Ewald Weibel and George Palade more than 50 years ago [1]
Summary
Endothelial cells represent the inner lining of blood vessels and form the principal border between vasculature and tissues. While resting endothelial cells present an anti-coagulant surface to circulating cells of the vasculature, endothelial activation converts this surface to a pro-coagulant and pro-inflammatory one capable of capturing platelets and leukocytes This transition critically depends on the acute and tightly regulated exposure of adhesion molecules, most notably von-Willebrand factor (VWF) and P-selectin, which serve as receptors for platelets and leukocytes, respectively, and are stored in large secretory granules of endothelial cells, the Weibel-Palade bodies (WPB) discovered in electron microscopy sections of arterial endothelia by Ewald Weibel and George Palade more than 50 years ago [1]. Following inflammatory stimulation of endothelial cells, P-selectin is externalized via regulated WPB exocytosis and provides binding sites for P-selectin ligands on the surface of circulating leukocytes This initiates their tethering and rolling as a prerequisite for firm adhesion and subsequent extravasation. Significant phenomenological differences exist between the Ca2+ and cAMP dependent release pathways but fairly little is known about underlying mechanisms and cross-talk between the pathways
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