Direct effects of cigarette smoke in pulmonary arterial cells: Implications in arterial remodeling and vascular tone maintenance

Abstract

Smoking 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. However, its direct effects on pulmonary vasculature have not been studied in deep, in part due to the classic conception that vascular damage is a consequence of alveolar hypoxia and loss of capillary bed. We have used different molecular and cell biology approaches, as well as tissue studies from in vivo models and human samples to analyse how cigarette smoke extract (CSE) regulated pulmonary arterial cells phenotypic modulation, particularly on human fibroblasts and smooth muscle cells. Our results demonstrate that CSE exposure has direct effects on hPAFib and hPASMC, promoting a senescent phenotype that in turn contributes to increase the proliferative potential of non-exposed cells. Using traction force microscopy, wire myography and patch-clamp techniques, we demonstrate that CSE affects cell contractility and dysregulates the expression and activity of the voltage-gated K+ channel Kv7.4. This ultimately contributes to limit vascular responses impairing vasoconstriction and endothelium-dependent and independent relaxation. Additionally, the levels of this channel are diminished in the lungs of smoke-exposed mice and COPD patients. These findings greatly enhance knowledge about pulmonary diseases, in particular COPD, and open a new line of study related to the exploitation of these mechanisms as therapeutic targets.