As the first discovered gaseous signaling molecule, nitric oxide (NO) affects a number of cellular processes, including those involving vascular cells. This brief review summarizes the contribution of NO to the regulation of vascular tone and its sources in the blood vessel wall. NO regulates the degree of contraction of vascular smooth muscle cells mainly by stimulating soluble guanylyl cyclase (sGC) to produce cyclic guanosine monophosphate (cGMP), although cGMP-independent signaling [S-nitrosylation of target proteins, activation of sarco/endoplasmic reticulum calcium ATPase (SERCA) or production of cyclic inosine monophosphate (cIMP)] also can be involved. In the blood vessel wall, NO is produced mainly from l-arginine by the enzyme endothelial nitric oxide synthase (eNOS) but it can also be released non-enzymatically from S-nitrosothiols or from nitrate/nitrite. Dysfunction in the production and/or the bioavailability of NO characterizes endothelial dysfunction, which is associated with cardiovascular diseases such as hypertension and atherosclerosis.

Endothelial cells control vascular tone by releasing nitric oxide (NO) produced by endothelial NO synthase. The activity of endothelial NO synthase is modulated by the calcium concentration and by post-translational modifications (eg, phosphorylation). When NO reaches vascular smooth muscle, soluble guanylyl cyclase is its primary target producing cGMP. NO production is stimulated by circulating substances (eg, catecholamines), platelet products (eg, serotonin), autacoids formed in (eg, bradykinin) or near (eg, adiponectin) the vascular wall and physical factors (eg, shear stress). NO dysfunction can be caused, alone or in combination, by abnormal coupling of endothelial cell membrane receptors, insufficient supply of substrate ( l -arginine) or cofactors (tetrahydrobiopterin), endogenous inhibitors (asymmetrical dimethyl arginine), reduced expression/presence/dimerization of endothelial NO synthase, inhibition of its enzymatic activity, accelerated disposition of NO by reactive oxygen species and abnormal responses (eg, biased soluble guanylyl cyclase activity producing cyclic inosine monophosphate) of the vascular smooth muscle. Major culprits causing endothelial dysfunction, irrespective of the underlying pathological process (aging, obesity, diabetes mellitus, and hypertension), include stimulation of mineralocorticoid receptors, activation of endothelial Rho-kinase, augmented presence of asymmetrical dimethyl arginine, and exaggerated oxidative stress. Genetic and pharmacological interventions improve dysfunctional NO-mediated vasodilatations if protecting the supply of substrate and cofactors for endothelial NO synthase, preserving the presence and activity of the enzyme and reducing reactive oxygen species generation. Common achievers of such improvement include maintained levels of estrogens and increased production of adiponectin and induction of silent mating-type information regulation 2 homologue 1. Obviously, endothelium-dependent relaxations are not the only beneficial action of NO in the vascular wall. Thus, reduced NO-mediated responses precede and initiate the atherosclerotic process.

RNA interference (RNAi) is a potent and specific post-transcriptional gene silencing process. Since its discovery, tremendous efforts have been made to translate RNAi technology into therapeutic applications for the treatment of different human diseases including respiratory diseases, by manipulating the expression of disease-associated gene(s). Similar to other nucleic acid-based therapeutics, the major hurdle of RNAi therapy is delivery. Pulmonary delivery is a promising approach of delivering RNAi therapeutics directly to the airways for treating local conditions and minimizing systemic side effects. It is a non-invasive route of administration that is generally well accepted by patients. However, pulmonary drug delivery is a challenge as the lungs pose a series of anatomical, physiological and immunological barriers to drug delivery. Understanding these barriers is essential for the development an effective RNA delivery system. In this review, the different barriers to pulmonary drug delivery are introduced. The potential of RNAi molecules as new class of therapeutics, and the latest preclinical and clinical studies of using RNAi therapeutics in different respiratory conditions are discussed in details. We hope this review can provide some useful insights for moving inhaled RNAi therapeutics from bench to bedside.