Presenting Author University of California Davis Davis, California
Arterial myocytes receive many inputs from sympathetic nerves that regulate vascular reactivity by activating GS protein-coupled receptors (GSPCRs). The ubiquitous second messenger 3,5- cyclic adenosine monophosphate (cAMP) is synthesized by adenylyl cyclases (ACs) in response to the activation of various GSPCRs and plays a critical role in integrating the myriad of signals elicited. Importantly, arterial myocyte cAMP signaling has been traditionally linked with relaxation. We found that arterial myocytes from mice exposed to secondhand smoke (SHS) had an attenuated cAMP synthesis in response to the β-adrenergic receptor (βAR) agonist isoproterenol (ISO) (unpublished data), which could alter vascular reactivity. Tobacco smoke contains over 7,000 chemicals, including nicotine. Nicotine, the primary addictive component in tobacco cigarettes is a strong sympathomimetic with significant vasoactive effects and have been shown to alter cellular cAMP production. However, how nicotine impacts cAMP signaling in the vasculature, particularly in arterial myocytes, and the implications of these changes in vascular reactivity are unclear. We are tackling this knowledge gap by expressing a FRET-based cAMP biosensor in cultured arterial myocytes to determine cAMP signaling in response to nicotine/cotinine. We also developed a mouse expressing a new cAMP sensor specifically in SM (CamperSM) to investigate cAMP dynamics in native VSM/arteries. We hypothesize that nicotine impairs receptor-mediated cAMP signaling in arterial myocytes leading to altered vascular reactivity. Our data using unpassaged arterial myocytes expressing a cytosolic FRET-based cAMP sensor exposed to cotinine (the primary metabolite of nicotine) show a reduction in ISOinduced cAMP production. Similar results were observed in arterial myocytes from CAMPERSM mice infused with nicotine. These results suggest similar effects of cotinine in vitro or nicotine in vivo on βAR-mediated cAMP synthesis in arterial myocytes. Intriguingly, we found that inhibition of phosphodiesterases rescue cAMP synthesis in CAMPERSM arterial myocytes exposed to nicotine. We correlated the nicotine-induced reduction in arterial myocytes cAMP synthesis with impaired vasodilation in response to ISO. Our data suggest that nicotine impairs receptormediated cAMP signaling in arterial myocytes leading to altered vascular reactivity. Nicotineinduced cAMP dysregulation leading to altered arterial myocytes excitability could be an underlying factor contributing to cardiovascular disease in individuals exposed to SHS and users of nicotine containing products.
Support or Funding Information
NHLBI, Training Program in Basic and Translational Cardiovascular Science (T32 HL086350)
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