Endogenous adrenomedullin protects against vascular response to injury in mice

Background - In our previous study, adrenomedullin ( AM) overexpression could limit the arterial intimal hyperplasia induced by cuff injury in rats. However, it remains to be elucidated whether endogenous AM plays a role against vascular injury. Methods and Results - We used the AM knockout mice to investigate the effect of endogenous AM. Compared with wild-type ( AM(+/+)) mice, heterozygous AM knockout (AM(+/-)) mice had the increased intimal thickening of the cuff-injured femoral artery, concomitantly with lesser AM staining. In AM(+/-) mice, cuff placement increased both the production of superoxide anions (O-2(-)) measured by coelentarazine chemiluminescence and the immunostaining of p67(phox) and gp91(phox), subunits of NAD(P)H oxidase in the adventitia, associated with the increment of CD45-positive leukocytes, suggesting that the stimulated formation of radical oxygen species accompanied chronic adventitial inflammation. Not only the AM gene transfection but also the treatment of NAD( P) H oxidase inhibitor apocynin and membrane-permeable superoxide dismutase mimetic tempol could limit cuff-induced intimal hyperplasia in AM(+/-) mice, associated with the inhibition of O-2(-) formation in cuff-injured artery. Conclusions - The overproduction of oxidative stress induced by the increased NAD( P) H oxidase activity might be involved in cuff-injured arterial intimal hyperplasia in AM(+/-) mice. Thus, it is suggested that endogenous AM possesses a protective action against the vascular response to injury, possibly through the inhibition of oxidative stress production.