Molecular Study on Physiological and Clinical Significance of Adrenomedullin

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Adrenomedullin (AM), a potent vasorelaxing and natriuretic peptide, is thought to act as an autocrine/paracrine regulator in the vasculature as well as in renal glomeruli and tubules.In cultured bovine aortic endothelial cells, we have shown that both shear stress and oxidative stress markedly augment the synthesis and secretion of AM. Using specific anti-AM monoclonal antibody we prepared, we have demonstrated that endogenous AM produced by the endothelium inhibits PDGF-induced cell proliferation and strongly downregulates the endothelin secretion in an autocrine manner, thereby potentially protecting against vascular insults. On the other hand, AM potently stimulated the proliferation and migration of quiescent human umbilical vein endothelial cells. Using gel plug assay and laser Doppler imaging, AM stimulated vascular formation in vivo as well. We have shown that these effects of AM are mediated via the cAMP/PKA/PI3K pathway. Furthermore, we have already succeeded in the identifica … More tion and establishment of vascular progenitor cells from mouse ES cells. Using this in vitro vasculogenesis model, we found that AM receptor components, RAMP2 and CRLR, are expressed from an early stages of vascular development, suggesting that AM may play a role in vasculogenesis in vivo.In the kidney, We have shown that a significant amount of AM is produced from mesangial cells. We have demonstrated that RAMP2 and CRLR are markedly upregulated during the progression of renal fibrosis using an obstructive nephropathy model. We also showed that injured renal tissues exhibited enhanced basal and AM-stimulated cAMP production, and addition of AM in cultured renal fibroblasts inhibited proliferation and TGF-β-stimulated extracellular matrix production in a cAMP-dependent fashion.These results suggest that AM potentially exerts protective effects in the vasculature, by enhancing endothelial repair and regeneration as well as probably angiogenesis, and in the kidney, by counteracting the fibrogenic stimuli such as TGF-β. In addition, the activation of AM and its receptor system during vascular and renal injury, if any, should play a role in modulating the process of vascular and renal remodeling, against the disease progression. Less