Adrenomedullin-RAMP2 System in Cardiovascular Development and Homeostasis

Abstract

Adrenomedullin (AM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic vasoactive molecule involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. To elucidate the in vivo roles of AM, we have established and analyzed genetically engineered AM mice and its receptor components. Heterozygotes of AM knockout mice (AM+/-) showed blood pressure elevation, severe cardiac hypertrophy, and fibrosis by pressure overload or angiotensin II infusion. On the other hand, vascular-specific AM-overexpressing mice were resistant to neointimal formation by arterial injury. Therefore, endogenous AM exerts protective effects against stress-induced cardiac hypertrophy, fibrosis, and arteriosclerosis, as well as a vasodilating effect. Homozygotes of AM knockout mice (AM-/-) were lethal at mid-gestation with abnormalities in vascular development. This finding first clarified the indispensable roles of AM in vascular development. We also showed that AM possesses novel angiogenic properties not only during development, but also in adults. Based on these observations, there is hope that AM can be used therapeutically. However, AM has a short half-life in the blood stream and its application in chronic disease has limitations. We generated knockout mice of receptor activitymodifying protein 2 (RAMP2), a small membrane protein that associates with the AM receptor. We found that the important vascular phenotypes of AM knockout mice were reproduced in RAMP2 knockout mice. This shows that RAMP2 is the key determinant of the vascular functions of AM. RAMP2 could be an attractive therapeutic target in cardiovascular diseases. Keywords: Angiogenesis, arteriosclerosis, cardiac hypertrophy, knockout mice, vascular development, pheochromocytoma, cardiovascular diseases, circulatory homeostasis, ischemic limb