UC Davis

Cyclic adenosine monophosphate (cAMP) plays a significant role in vascular smooth muscle (VSM) biology, including proliferation, and differentiation. Moreover, cAMP signaling regulates VSM contractility. For instance, agonists acting through -adrenergic receptors (-AR) produce vasodilation by triggering adenylyl cyclases (ACs) activity and increasing cAMP levels VSM. 1-8 It has been shown by our group that VSM from mice exposed to secondhand smoke (SHS) had an attenuated cAMP level in response to the β-AR agonist isoproterenol (ISO), resulting in altered vascular reactivity. Tobacco smoke (TS) contains over 7,000 chemicals, including nicotine. 9 Nicotine is the primary addictive component in tobacco cigarettes (TCs) and has been shown to alter cellular cAMP production. 10,11 Yet, how nicotine impacts cAMP signaling in the vasculature, particularly in VSM, and the implications of these changes in vascular reactivity are unclear. Here we addressed this knowledge gap by systematically evaluating the effects of nicotine on cAMP production in native VSM from mice. Firstly, we determined the effects of nicotine on ISO-induced β-AR-mediated cAMP levels using a mouse expressing a cAMP biosensor specifically in smooth muscle (CAMPERSM). Then we determined the vascular reactivity in vessels of mice infused with nicotine using wire myography. Finally, we determined the expression of key proteins involved in cAMP synthesis and degradation. These experiments were designed to understand how nicotine alters cAMP signaling and the physiological consequences of nicotine exposure at the artery level. Our findings suggest that nicotine alters ISO-induced cAMP levels in VSM from intact arteries. This was correlated with impaired VSM relaxation in response to ISO. Our studies show that the altered ISO-induced cAMP synthesis and VSM relaxation in nicotine-treated mice can be rescued by inhibiting phosphodiesterases (PDEs). We also found that nicotine-infused mice have a decrease in AC6 abundance, which could contribute to impaired ISO-induced cAMP levels in VSM. Overall, this study uncovered mechanisms mediating nicotine impairment of cAMP synthesis and VSM relaxation, which may underlie alterations in vascular function in people exposed to or using nicotine products.