Abstract 14486: Adrenomedullin-RAMP2 System Regulates Vascular Endothelial Integrity
Adrenomedullin (AM) is a peptide involved in both the pathogenesis of cardiovascular diseases and circulatory homeostasis. AM knockout mice (AM-/-) are lethal with edema and hemorrhage at mid-gestation, suggesting its critical roles during vascular development. We have shown that knockout mice of RAMP2 (RAMP2-/-), one of the accessory proteins of AM-receptor, are embryonic lethal at mid-gestation with the similar vascular abnormalities of AM-/- and AM expression is highly upregulated in RAMP2-/- as a compensatory manner. To analyze the pathophysiological roles of vascular AM-RAMP2 system directly, we generated vascular endothelial cell-specific RAMP2 knockout mice (E-RAMP2-/-) using Cre-loxP system. Although, E-RAMP2-/- survived beyond mid-gestation, most of them were lethal around perinatal period with systemic edema. All vascular component cells were kept, however E-RAMP2-/- embryos showed deformity of endothelial cells and their partial detachment from basement membrane. Contrary, a small number of E-RAMP2-/- can survive until adulthood. In the survived E-RAMP2-/-, RAMP2 expression in endothelial cells was kept at 20% of wild-type. E-RAMP2-/- adult mice were apparently normal at younger age, however adult mice showed wall-thinning and expansion of aortic diameter with disarray of smooth muscle cells as well as the severe deformity and detachment of endothelial cells. Moreover, adult E-RAMP2-/- showed spontaneous occurrence of vasculitis lesions throughout the body from about 6 month of age. E-RAMP2-/- also showed premature vascular senescence. As the consequence of the vascular lesions, E-RAMP2-/- showed spontaneous occurrence of various organ damages; liver cirrhosis, cardiac enlargement with fibrosis, hydronephrosis, polycystic change of kidney, and glomerulosclerosis, with enhanced oxidative stress. On the other hand, RAMP2-overexpressing endothelial cells with AM-treatment showed resistance against oxidative stress-induced cellular senescence. In conclusion, RAMP2 is the key determinant of the vascular functions of AM; RAMP2 is essential for the vaso- and organ-protective effects of AM in adult as well as for the angiogenesis during development.
- © 2011 by American Heart Association, Inc.