Adrenomedullin (AM), a member of the calcitonin peptide superfamily, is a peptide involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. Its receptor, calcitonin receptor-like receptor (CLR), associates with an accessory protein, receptor activity-modifying protein (RAMP). Depending upon which the three RAMP isoforms (RAMP1-3) it interacts with, CLR functions as a receptor for AM or other calcitonin family peptides. AM knockout mice (-/-) died mid-gestation due to abnormalities in vascular development. We found that phenotypes similar to AM-/- were reproduced only in RAMP2-/- mice. We generated endothelial cell-specific RAMP2 knockout mice (E-RAMP2-/-) and found most E-RAMP2-/- mice died perinatally. In surviving adults, vasculitis and organ fibrosis occurred spontaneously. We next generated drug-inducible cardiac myocyte-specific RAMP2-/- (DI-C-RAMP2-/-) mice, which exhibited dilated cardiomyopathy-like heart failure with cardiac dilatation and myofibril disruption. DI-C-RAMP2-/- hearts also showed changes in mitochondrial structure and downregulation of mitochondria-related genes involved in oxidative phosphorylation and β-oxidation. In contrast to RAMP2-/- mice, RAMP3-/- mice were born with no major abnormalities. In adult RAMP3-/- mice, postnatal angiogenesis was normal, but drainage of subcutaneous lymphatic vessels was delayed. RAMP3-/- mice also showed more severe interstitial edema than in wild-type mice in a tail lymphedema model. These findings show that the AM-RAMP system is a key determinant of cardiovascular integrity and homeostasis from prenatal stages through adulthood. The AM-RAMP2 system mainly regulates vascular development and homeostasis, while the AM-RAMP3 system mainly regulates lymphatic function in adults. The AM-RAMP system may thus have therapeutic potential for the treatment of cardiovascular diseases.