Adrenomedullin (AM) is a novel vasodilating
peptide involved in the regulation of circulatory homeostasis and implicated in the pathophysiology of
cardiovascular disease. We tested the hypothesis that AM also possesses angiogenic properties. Using
laser Doppler perfusion imaging, we found that AM stimulated recovery of blood flow to the affected limb in the mouse hind-limb
ischemia model. AM exerted this effect in part by promoting expression of
vascular endothelial growth factor (
VEGF) in the ischemic limb, and immunostaining for CD31 showed the enhanced flow to reflect increased collateral capillary density. By enhancing
tumor angiogenesis, AM also promoted the growth of subcutaneously transplanted
sarcoma 180 tumor cells. However, heterozygotic AM knockout mice (AM+/-) showed significantly less blood flow recovery with less collateral capillary development and
VEGF expression than their wild-type littermates. Similarly, mice treated with
AM22-52, a competitive inhibitor of AM, showed reduced capillary development, and growth of
sarcoma 180 tumors was inhibited in AM+/- and AM22-52-treated mice. Notably, administration of
VEGF or AM rescued blood flow recovery and capillary formation in AM+/- and AM22-52-treated mice. In cocultures of endothelial cells and fibroblasts, AM enhanced
VEGF-induced capillary formation, whereas in cultures of endothelial cells AM enhanced
VEGF-induced Akt activation. These results show that AM possesses novel angiogenic properties mediated by its ability to enhance
VEGF expression and Akt activity. This may make AM a useful therapeutic tool for relieving
ischemia; conversely, inhibitors of AM could be useful for clinical management of
tumor growth.