Vascular abnormalities and elevated blood pressure in mice lacking adrenomedullin gene

Background-Adrenomedullin (AM) is a vasodilating peptide involved in the re gulation of circulatory homeostasis and in the pathophysiology of certain c ardiovascular diseases. Levels of AM are markedly increased in the fetoplac ental circulation during pregnancy, although its function there remains unk nown. To clarify the physiological functions of AM, we chose a gene-targeti ng strategy in mice. Methods and Results-Targeted null mutation of the AM gene is lethal in uter o: the mortality rate among AM(-/-) embryos was > 80% at E13.5. The most ap parent abnormality in surviving AM(-/-) embryos at E13.5 to E14.0 was sever e hemorrhage, readily observable under the skin and in visceral organs. Hem orrhage was not detectable at E12.5 to E13.0, although the yolk sac lacked well-developed vessels. Electron microscopic examination showed endothelial cells to be partially detached from the basement structure at E12.5 in vit elline vessels and hepatic capillaries, which allowed efflux of protoerythr ocytes through the disrupted barrier. The basement membrane was not clearly recognizable in the aorta and cervical artery, and the endothelial cells s tood out from the wall of the lumen, only partially adhering to the basemen t structure. AM(+/-) mice survived to adulthood but exhibited elevated bloo d pressures with diminished nitric oxide production. Conclusions-AM is indispensable for the vascular morphogenesis during embry onic development and for postnatal regulation of blood pressure by stimulat ing nitric oxide production.