Novel relaxants of pulmonary arteries and airways are of special interest to obtain insights into pulmonary signaling pathways and to develop treatment strategies for lung diseases. Herein, we demonstrate that Arg-Gly-Asp (RGD) peptides induce a dose-dependent relaxation of pulmonary arteries and airways in mouse. The relaxing effect was specific because it was strongly reduced using the control peptides RGE or RAD (P<0.001). Longer peptide sequences containing RGD and its flanking amino acids found in fibronectin showed a similar effect even at a 10-fold lower concentration. The relevance of RGD-induced pulmonary vasorelaxation was demonstrated in isometric force measurements, lung slices, and the isolated perfused lung model under normoxia and hypoxia and in vivo. As cell surface receptor we identified β3- but not β1-integrin subunits. Moreover, vasorelaxation by RGD peptides was strongly diminished after removal of the endothelium in endothelial nitric oxide synthase-deficient (eNOS(-/-) mice; P<0.01) and after pharmacological inhibition of the NO/sGC pathway (P<0.05). Additionally, several potassium channels like Kv, Kir, and KATP played a role. In airways the response was mediated by Kv and KCa channels. Thus, RGD peptides are relaxants of pulmonary arteries and airways. These findings may help to establish novel therapeutic approaches for pulmonary hypertension and obstructive lung disease.
Keywords: endothelial nitric oxide synthase; hypoxia; pulmonary vascular tone.