Tobacco smoke is the main risk factor for the development of chronic obstructive pulmonary disease (COPD). Despite current therapies alleviate symptoms there are limitations in the efficacy of treatments to curb its cardiovascular morbidities, particularly vascular dysfunction and the development of pulmonary hypertension. Our previous studies demonstrate that cigarette smoke directly contributes to pulmonary arterial dysfunction. Nevertheless, a further characterization of the molecular basis involved is needed for more effective targeted treatment. We have performed in vitro analysis with human pulmonary artery smooth muscle cells (hPASMC) challenged with cigarette smoke extract, and in vivo approaches of tobacco exposure in murine models and transgenic mice. Furthermore, we extended our analysis to include hPASMCs from COPD patients compared to non-COPD individuals, as well as pulmonary arteries from human tissue samples. These approaches allowed us to explore the molecular pathways contributing to the harmful effects from oxidative stress, calcium dysregulation and disruptions to the contractile machinery of pulmonary artery smooth muscle cells. Interestingly, these effects were triggered by the activation of nicotinic acetylcholine receptors (nAChRs) in these cells. Additionally, we demonstrated that nAChR antagonists or alpha 7 nAChR deletion in a murine model effectively protected pulmonary artery function from damage. Most importantly, alpha 7 nAChR expression in pulmonary arteries of COPD patients rose with disease severity and showed an inverse correlation with respiratory function. These findings have important clinical implications, indicating that nAChR-targeted tailored antagonists could be a promising therapeutic strategy for COPD-related vascular dysfunction.