Intercellular signaling by cyclic AMP-containing microparticles

Microparticles (MPs) are extracellular vesicles 0.1 to 1 um in diameter that are released from many cell types under physiological and pathophysiological conditions. Endothelial-derived MPs are found circulating in blood and communicate with downstream target cells in a paracrine fashion. MPs contain a variety of functional protein and RNA that are likely to contribute to the information content delivered to target cells by MPs. The Bauer and Sayner laboratories recently determined that cyclic adenosine monophosphate (cAMP), a ubiquitous second messenger, is found in MPs from pulmonary microvascular endothelial cells (PMVECs); ongoing studies suggest that MPs isolated from PMVECs treated with p adrenergic agonists have increased cAMP levels. We developed mathematical models of MP-target cell interactions in order to better understand how cAMP and enzymes in the cAMP signaling pathway delivered by MPs may alter target cell signaling. Simulations indicate that if cAMP contained in one MP were released into a near-membrane compartment of a target cell, cAMP levels within that compartment would be sufficient to activate protein kinase A for several minutes. However, if cAMP were released into the larger volume of the bulk cytoplasm it would have little or no effect on target cell function. These data indicate that a single MP may deliver cAMP payloads sufficient to trigger sustained responses in a target cell and may contribute to MP-mediated signaling events.