Adrenomedullin provokes endothelial Akt activation and promotes vascular regeneration both in vitro and in vivo.
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.
Miyashita
Kazutoshi
K
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho Sakyo-ku, Japan.
Itoh
Hiroshi
H
Sawada
Naoki
N
Fukunaga
Yasutomo
Y
Sone
Masakatsu
M
Yamahara
Kenichi
K
Yurugi-Kobayashi
Takami
T
Park
Kwijun
K
Nakao
Kazuwa
K
D053607:Adrenomedullin; D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology; D015153:Blotting, Western; D002455:Cell Division; D002465:Cell Movement; D002478:Cells, Cultured; D003094:Collagen / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004727:Endothelium / Q000502:physiology; D004730:Endothelium, Vascular / Q000166:cytology*; D004789:Enzyme Activation; D006801:Humans; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D018919:Neovascularization, Physiologic; D010455:Peptides / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D012038:Regeneration; D013997:Time Factors; D014945:Wound Healing
D053607:Adrenomedullin; D001672:Biocompatible Materials; D003094:Collagen; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004338:Drug Combinations; D007797:Laminin; D010455:Peptides; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C059485:matrigel; C494918:AKT1 protein, human