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

Xiao, Jie; Zhang, Ben; Su, Zhengchen; Liu, Yakun; Shelite, Thomas R.; Chang, Qing; Qiu, Yuan; Bei, Jiani; Wang, Pingyuan; Bukreyev, Alexander; Soong, Lynn; Jin, Yang; Ksiazek, Thomas; Gaitas, Angelo; Rossi, Shannan L.; Zhou, Jia; Laposata, Michael; Saito, Tais B.; Gong, Bin

Coagulopathy is associated with both inflammation and infection, including infection with novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. Clot formation is promoted via cyclic adenosine monophosphate (cAMP)-mediated secretion of von Willebrand factor (vWF), which fine tunes the process of hemostasis. The exchange protein directly activated by cAMP (EPAC) is a ubiquitously expressed intracellular cAMP receptor that plays a regulatory role in suppressing inflammation. To assess whether EPAC could regulate vWF release during inflammation, we utilized our EPAC1-null mouse model and revealed increased secretion of vWF in endotoxemic mice in the absence of the EPAC1 gene. Pharmacological inhibition of EPAC1 in vitro mimicked the EPAC1-/- phenotype. In addition, EPAC1 regulated tumor necrosis factor-α (TNFα)-triggered vWF secretion from human umbilical vein endothelial cells (HUVECs) in a manner dependent upon inflammatory effector molecules phosphoinositide 3-kinase (PI3K) and endothelial nitric oxide synthase (eNOS). Furthermore, EPAC1 activation reduced inflammation-triggered vWF release, both in vivo and in vitro. Our data delineate a novel regulatory role for EPAC1 in vWF secretion and shed light on the potential development of new strategies to control thrombosis during inflammation.