Adrenomedullin can protect against pulmonary vascular remodeling induced by hypoxia

Background-Chronic hypoxia is one of the major causes of pulmonary vascular remodeling associated with stimulating reactive oxygen species (ROS) production. Recent studies have indicated that hypoxia upregulates expression of adrenomedullin ( AM), which is not only a potent vasodilator but also an antioxidant. Thus, using heterozygous AM-knockout (AM(+/-)) mice, we examined whether AM could attenuate pulmonary vascular damage induced by hypoxia. Methods and Results-Ten-week-old male wild-type (AM(+/+)) or AM(+/-) mice were housed under 10% oxygen conditions for 3 to 21 days. In AM(+/-) mice, hypoxia enhanced AM mRNA expression, which was reduced by the administration of a superoxide dismutase mimetic, 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl (hydroxy-TEMPO). Hypoxia induced pulmonary vascular remodeling, which was associated with the increased production of oxidative stress measured by electron spin resonance and immunostaining of 3-nitrotyrosine. The media wall thickness of the pulmonary arteries was significantly greater in AM(+/-) mice housed under hypoxia than in AM(+/+) mice under hypoxia. Concomitantly, pulmonary ROS production induced by hypoxia was more enhanced in AM(+/-) mice than in AM(+/+) mice. The administration of both exogenous AM and hydroxy-TEMPO normalized pulmonary vascular media wall thickness in not only AM(+/+) but also AM(+/-) mice under hypoxic conditions associated with the normalization of ROS overproduction in the lung. Conclusions-The present results suggest that an endogenous AM is a potential protective peptide against hypoxia-induced vascular remodeling, possibly through the suppression of ROS generation, which might provide an effective therapeutic strategy.