Transforming growth factor-β modulates the expression of nitric oxide signaling enzymes in the injured developing lung and in vascular smooth muscle cells

Abstract

Nitric oxide signaling has an important role in regulating pulmonary development and function. Expression of soluble guanylate cyclase (sGC) and cGMP-dependent protein kinase I (PKGI), both critical mediators of nitric oxide (NO) signaling, is diminished in the injured newborn lung through unknown mechanisms. Recent studies suggest that excessive transforming growth factor-β (TGF-β) activity inhibits injured newborn lung development. To explore mechanisms that regulate pulmonary NO signaling, we tested whether TGF-β decreases sGC and PKGI expression in the injured developing lung and pulmonary vascular smooth muscle cells (SMC). We found that chronic oxygen-induced lung injury decreased pulmonary sGCα1and PKGI immunoreactivity in mouse pups and that exposure to a TGF-β-neutralizing antibody prevented this reduction of sGC and PKGI protein expression. In addition, TGF-β1decreased expression of NO signaling enzymes in freshly isolated pulmonary microvascular SMC/myofibroblasts, suggesting that TGF-β has a direct role in modulating NO signaling in the pup lung. Moreover, TGF-β1decreased sGC and PKGI expression in pulmonary artery and aortic SMC from adult rats and mice, suggesting a general role for TGF-β in modulating NO signaling in vascular SMC. Although other cytokines decrease sGC mRNA stability, TGF-β did not modulate sGCα1or PKGIβ mRNA turnover in vascular SMC. These studies indicate for the first time that TGF-β decreases NO signaling enzyme expression in the injured developing lung and pulmonary vascular SMC. Moreover, they suggest that TGF-β-neutralizing molecules might counteract the effects of injury on NO signaling in the newborn lung.