EPAC regulates von Willebrand factor secretion from endothelial cells in a PI3K/eNOS-dependent manner during inflammation

Xiao, J.; Zhang, B.; Su, Z.; Liu, Y.; Shelite, T. R.; Chang, Q.; Wang, P.; Bukreyev, A.; Soong, L.; Jin, Y.; Ksiazek, T.; Gaitas, A.; Rossi, S. L.; Zhou, J.; Laposata, M.; Saito, T. B.; Gong, B.

doi:10.1101/2020.09.04.282806

bioRxiv · 10.1101/2020.09.04.282806

EPAC regulates von Willebrand factor secretion from endothelial cells in a PI3K/eNOS-dependent manner during inflammation

Xiao, J.·Zhang, B.·Su, Z.·Liu, Y.·Shelite, T. R.·Chang, Q.·Wang, P.·Bukreyev, A.·Soong, L.·Jin, Y.·Ksiazek, T.·Gaitas, A.·Rossi, S. L.·Zhou, J.·Laposata, M.·Saito, T. B.·Gong, B.

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Abstract

Coagulopathy is associated with both inflammation and infection, including infection with the novel SARS-CoV-2 (COVID-19). Endothelial cells (ECs) fine tune hemostasis via cAMP-mediated secretion of von Willebrand factor (vWF), which promote the process of clot formation. The exchange protein directly activated by cAMP (EPAC) is a ubiquitously expressed intracellular cAMP receptor that plays a key role in stabilizing ECs and suppressing inflammation. To assess whether EPAC could regulate vWF release during inflammation, we utilized our EPAC1-null mouse model and revealed an increased secretion of vWF in endotoxemic mice in the absence of the EPAC1 gene. Pharmacological inhibition of EPAC1 in vitro mimicked the EPAC1-/- phenotype. EPAC1 regulated TNF-triggered vWF secretion from human umbilical vein endothelial cells (HUVECs) in a phosphoinositide 3-kinases (PI3K)/endothelial nitric oxide synthase (eNOS)-dependent manner. Furthermore, EPAC1 activation reduced inflammation-triggered vWF release, both in vivo and in vitro. Our data delineate a novel regulatory role of EPAC1 in vWF secretion and shed light on potential development of new strategies to controlling thrombosis during inflammation. Key PointPI3K/eNOS pathway-mediated, inflammation-triggered vWF secretion is the target of the pharmacological manipulation of the cAMP-EPAC system.

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Xiao, J., Zhang, B., Su, Z., Liu, Y., Shelite, T. R., Chang, Q., Wang, P., Bukreyev, A., Soong, L., Jin, Y., Ksiazek, T., Gaitas, A., Rossi, S. L., Zhou, J., Laposata, M., Saito, T. B., Gong, B.. 2020-09-04. EPAC regulates von Willebrand factor secretion from endothelial cells in a PI3K/eNOS-dependent manner during inflammation. https://doi.org/10.1101/2020.09.04.282806

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