The Epac-Rap1 Signaling Pathway Controls cAMP-mediated Exocytosis of Weibel-Palade Bodies in Endothelial Cells

Abstract

Background: Ca 2ϩ -and cAMP-raising agonists promote exocytosis of Weibel-Palade bodies from endothelial cells. Results: cAMP-mediated Weibel-Palade body release depends on Rap1 activation by the exchange protein activated by cAMP (Epac). Conclusion:The Epac-Rap1 pathway is involved in the regulation of cAMP-mediated Weibel-Palade body release. Significance: We unraveled a new signaling cascade that regulates cAMP-mediated Weibel-Palade body exocytosis and systemic VWF levels in plasma.

Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall

“…Exocytosis can also be activated independently of PKA activity through a cAMP-induced activation of Rap1 (Ras-related protein 1) mediated by the guanine nucleotide exchange factor Epac (van Hooren et al, 2012). It is noteworthy that activation of both Rap1 and RalA pathways may be coordinated, allowing both pathways to contribute to the exocytotic process in a synchronous fashion (van Hooren et al, 2012).…”

“…The exocytosis of WPBs caused by an increase in cAMP is partly due to a PKA-dependent signaling pathway, which leads to the activation of RalA (de Leeuw et al, 1999;Rondaij et al, 2004Rondaij et al, , 2008. Exocytosis can also be activated independently of PKA activity through a cAMP-induced activation of Rap1 (Ras-related protein 1) mediated by the guanine nucleotide exchange factor Epac (van Hooren et al, 2012). It is noteworthy that activation of both Rap1 and RalA pathways may be coordinated, allowing both pathways to contribute to the exocytotic process in a synchronous fashion (van Hooren et al, 2012).…”

Syntaxin-binding protein STXBP5 inhibits endothelial exocytosis and promotes platelet secretion

“…Recent studies have defined some of the endothelial proteins that control vesicle secretory pathway in ECs. Syntaxins, vesicle-associated membrane proteins (VAMPs), synaptosomalassociated proteins (SNAPs), NSF, α-synuclein, and various small GTPases and their effectors (such as Rab11, RalA, Rap1, Rab27a, MyRIP, and Slp4-a) play a critical role in endothelial granule exocytosis (27)(28)(29)(30)(31)(32)(33)(34); NO and thioredoxin regulate exocytosis by chemically modifying NSF (35,36); and an assortment of secretagogues or pathologic stimuli can stimulate granule secretion from human…”

Purinergic A2b Receptor Activation by Extracellular Cues Affects Positioning of the Centrosome and Nucleus and Causes Reduced Cell Migration

“…Stimulation of the ␤-adrenergic receptor by isoproterenol or epinephrine causes production of cAMP, which activates Epac, not PKA (58,59). Compartmentalization in local microdomains was shown for cAMP and PKA (60,61) and may be involved in Epac activation.…”