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Cigarette Smoke Directly Promotes Pulmonary Arterial Remodeling and Kv7.4 Channel Dysfunction.

RATIONALE
Cigarette smoke is considered the chief leading cause of chronic obstructive pulmonary disease (COPD). Its impact on the progressive deterioration of the airways has been extensively studied, but its direct effects on pulmonary vasculature are less known.


OBJECTIVES
We aim to prove that pulmonary arterial remodeling in COPD patients is not just a consequence of alveolar hypoxia, but it is also due to direct effects of cigarette smoke on the pulmonary vascular bed.


METHODS
We have used different molecular and cell biology approaches, as well as traction force microscopy, wire myography and patch-clamp techniques in human cells and freshly isolated pulmonary arteries. Additionally, we relied on in vivo models and human samples to analyze the effects of cigarette smoke on pulmonary vascular tone alterations.


MEASUREMENTS AND MAIN RESULTS
Cigarette smoke extract (CSE) exposure directly promoted a hypertrophic, senescent phenotype that in turn contributed, through the secretion of inflammatory molecules, to increase the proliferative potential of non-exposed cells. Interestingly, these effects were significantly reversed by antioxidants. Furthermore, CSE affected cell contractility and dysregulated the expression and activity of the voltage-gated K+ channel Kv7.4. This contributed to impair vasoconstriction and vasodilation responses. Most importantly, the levels of this channel were diminished in the lungs of smoke-exposed mice, smokers and COPD patients.


CONCLUSIONS
Cigarette smoke directly contributes to pulmonary arterial remodeling through increased cell senescence, as well as vascular tone alterations due to diminished levels and function of the Kv7.4 channel. Strategies targeting these pathways may lead to novel therapies for COPD.