Abstract
Cyclic AMP (cAMP) is an important physiological second messenger that plays a central role in arterial myocyte excitability. While it is well-known that cAMP production by different Gs protein coupled receptors (GsPCRs) is confined to discrete subcellular compartments in many excitable cells, it is unclear if and how this spatial organization occurs in arterial myocytes that wrap around blood vessels. We hypothesized that ligand-induced cAMP signals are compartmentalized in arterial myocytes. Here, live-cell imaging with new targeted cAMP FRET-based (CUTie) biosensors was used to visualize cAMP signals in male and female human and mouse arterial myocytes. We found that receptor-mediated cAMP production was compartmentalized within the sarcoplasmic reticulum (SR) region of male, but not female arterial myocytes. PLA imaging suggested SR is closely associated with phosphodiesterase 4 (PDE4) and further analysis revealed that basal PDE4D expression was significantly higher in male arterial myocytes, which may contribute to spatially restricted subcellular cAMP signaling. Intriguingly, PDE4 activity was found to modulate SR Ca2+ load, as well as receptor-mediated vasorelaxation and blood flow (BF) in male arteries. These findings established a key role for PDE4 in regulating unique sexually dimorphic cAMP compartmentalization in arterial myocytes.
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