Subcellular signaling in the endothelium: cyclic nucleotides take their place

When lecturing on the topic of cellular signaling I have had occasion to ask the class for examples of cellular processes NOT impacted by cyclic AMP (cAMP) and am struck by how few examples exist. Indeed, studies spanning the past 60 years have detailed how this ubiquitous second messenger impacts virtually all cellular processes, including intermediary metabolism, contractility, motility, proliferation, and gene expression in most mammalian cells. Since the hydrophobic cAMP could in principle diffuse rapidly throughout the cell once formed, the remarkable spatial and temporal specificity of its numerous actions in cells is truly impressive. Herein I introduce the main players involved in coordinating actions of cAMP in vascular endothelial cells (VECs), and focus on the increasing awareness of the dominant role that cyclic nucleotide phosphodiesterases (PDEs), the sole cellular enzymes capable of hydrolytically inactivating cAMP, play in fostering this specificity.

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► VECs regulate coagulation, thrombosis, inflammation, vascular tone and remodeling.
► cAMP-signaling selectively influences these distinct VEC functions.
► Selectivity is coordinated through cAMP-signaling complexes (“cAMP-signalosomes”).
► Therapeutics aimed at cAMP-signalosomes will provide greater specificity.