Cigarette smoke extract increases expression and plasma membrane trafficking of α2C ‐ adrenoceptors in human microvascular smooth muscle cells

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Vasoconstriction of cutaneous arterioles in response to cold temperatures or emotion is a normal adaptive process in which the body diverts blood flow from the superficial circulation to internal organs to prevent heat loss. This is mediated by increased sympathetic activation as well as increased sensitivity of the digital arteriolar vascular smooth muscle to vasoconstrictors. When cold‐induced constriction is exacerbated, Raynaud’s phenomenon (RP) is precipitated. Remarkably, the entirety of this augmented cold‐induced vasoconstriction is mediated by α2Cadrenoceptors (α2C‐ARs) . We have previously established that cooling induces translocation of α2C‐ARs from the Golgi compartment, where they are trapped, to the plasma membrane of microvascular smooth muscle cells.Epidemiological studies show that cigarette smoking is a significant risk factor for RP. Here, we provide exciting evidence which shows that cigarette smoke extract (CSE) increases α2C‐AR protein expression in a concentration and time‐dependent manner in human arteriolar smooth muscle cells. This expression appears to be due to increased transcriptional activity of the α2C‐AR promoter since pretreatment with actinomcyin D, a transcription inhibitor, abolished CSE‐induced α2C‐AR protein expression. Moreover, CSE increased transcriptional activity of α2C‐AR promoter: reporter construct. Interestingly, apocynin, a ROS scavenger, abolished CSE‐induced α2C‐AR protein expression, indicative of a ROS‐mediated pathway. CSE also increased RhoA activation, a pathway that we have previously established to drive trafficking of α2C‐ARs to the membrane. Indeed, CSE evoked mobilization of α2C‐ARs to the cell membrane. Taken together, these results may explain the underlying mechanism of CSE‐exacerbated cold‐induced vasoconstriction and provide an alternative avenue for treatment of patients who have RP and are smokers.Support or Funding InformationThis publication was made possible by an MPP fund (#320133) from the American University of Beirut to Ali Eid