3P-0622 Adrenomedullin provokes endothelial Akt activation and promotes vascular regeneration both in vitro and in vivo

Department of Medicine and Clinical Science, Kyoto University, Kioto, Kyōto, Japan
FEBS Letters (Impact Factor: 3.17). 07/2003; 544(1-3):86-92. DOI: 10.1016/S1567-5688(03)90843-9
Source: PubMed


We previously reported that adrenomedullin (AM), a vasodilating hormone secreted from blood vessels, promotes proliferation and migration of human umbilical vein endothelial cells (HUVECs). In this study, we examined the ability of AM to promote vascular regeneration. AM increased the phosphorylation of Akt in HUVECs and the effect was inhibited by the AM antagonists and the inhibitors for protein kinase A (PKA) or phosphatidylinositol 3-kinase (PI3K). AM promoted re-endothelialization in vitro of wounded monolayer of HUVECs and neo-vascularization in vivo in murine gel plugs. These effects were also inhibited by the AM antagonists and the inhibitors for PKA or PI3K. The findings suggest that AM plays significant roles in vascular regeneration, associated with PKA- and PI3K-dependent activation of Akt in endothelial cells, and possesses therapeutic potential for vascular injury and tissue ischemia.


Available from: Naoki Sawada, Mar 06, 2014
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    • "Xenografts or the injection of tumour cells, which have been engineered to over-express AM into susceptible mice, can lead to tumour formation (Martinez et al. 2002, Oehler et al. 2002). Furthermore, agents that reduce the activity of AM such as the peptide antagonist AM 22–52 and agents that bind directly to AM reduce endothelial cell proliferation, migration, angiogenesis, tumour vascularisation and tumour growth (Ishikawa et al. 2003, Miyashita et al. 2003a, Iimuro et al. 2004, Schwarz et al. 2006, Roldos et al. 2008, Tsuchiya et al. 2010). For example, tumour weight was reduced compared with control following intratumoural injection of AM 22–52 in a mouse model of in vivo pancreatic cancer cell growth (Ishikawa et al. 2003). "
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    • "It acts through the G protein-coupled receptor calcitonin-like receptor (CLR), its specificity for AM being conferred by dimerization with the receptor activity modifying protein 2 (RAMP2) or 3 (RAMP3) (Poyner et al., 2002) leading to the AM1 and AM2 receptors, respectively. The angiogenic activity of AM has been reported to be mediated mainly by its binding to the AM1 receptor (Albertin et al., 2006; Guidolin et al., 2008) and involves the activation of mitogen-activated protein kinase and Akt cascades in EC (Kim et al., 2003; Miyashita et al., 2003). It has also been suggested (Guidolin et al., 2008) that these key signaling events, mediating the trophic action of the peptide, could be triggered by a transactivation of the vascular endothelial growth factor (VEGF)-receptor 2 (KDR) as a consequence of the binding of AM to its AM1 receptor. "
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