Adrenomedullin (ADM), originally identified as a vasodilating peptide, is now recognized to be a pleiotropic
molecule involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis.
Homozygotes of ADM knockout mice (ADM-/-) were lethal at mid-gestation with abnormalities of vascular development
and this finding clarified the angiogenic potency of ADM. Calcitonin gene-related peptide (CGRP), which has a structure
and function similar to that of ADM, has been identified as a family peptide of ADM. Unlike ADM-/-, CGRP-/- were apparently
normal. Therefore, the study of knockout mice first clarified the distinctly different physiological roles between
ADM and CGRP.
In contrast, heterozygotes of ADM knockout mice (ADM+/-) were alive but showed blood pressure elevation, reduced
neovascularization, and enhanced neointimal formation by arterial injury.
Based on these observations, there was hope ADM would have a therapeutic use. However, ADM has a short half-life in
the blood stream and its application in chronic disease has limitations. Therefore, we focused on the ADM receptor system.
The calcitonin-receptor-like receptor (CLR), which is the ADM receptor, associates with one of the accessory proteins,
called receptor activity-modifying proteins (RAMPs). By interacting with RAMP1, CLR exhibits a high affinity for
CGRP, whereas by interacting with either RAMP2 or -3, CLR exhibits a high affinity for ADM.
We generated RAMP knockout mice and found that vascular phenotypes similar to ADM-/- were reproduced only in
RAMP2-/-. This shows that RAMP2 is the key determinant of the vascular functions of ADM. RAMP2 could be an attractive
therapeutic target in cardiovascular diseases.