AMP-activated protein kinase (AMPK) signaling in endothelial cells is essential for angiogenesis in response to hypoxic stress.
AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that is regulated by hypoxia and other cellular stresses that result in diminished cellular ATP levels. Here, we investigated whether AMPK signaling in endothelial cells has a role in regulating angiogenesis. Hypoxia induced the activating phosphorylation of AMPK in human umbilical vein endothelial cells (HUVECs), and AMPK activation was required for the maintenance of pro-angiogenic Akt signaling under these conditions. Suppression of AMPK signaling inhibited both HUVEC migration to VEGF and in vitro differentiation into tube-like structures in hypoxic, but not normoxic cultures. Dominant-negative AMPK also inhibited in vivo angiogenesis in Matrigel plugs that were implanted subcutaneously in mice. These data identify AMPK signaling as a new regulator of angiogenesis that is specifically required for endothelial cell migration and differentiation under conditions of hypoxia. As such, endothelial AMPK signaling may be a critical determinant of blood vessel recruitment to tissues that are subjected to ischemic stress.
Nagata
Daisuke
D
Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Mogi
Masaki
M
Walsh
Kenneth
K
D055372:AMP-Activated Protein Kinases; D001672:Biocompatible Materials; D002196:Capillaries / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen; D004338:Drug Combinations; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D000860:Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D007797:Laminin; D009097:Multienzyme Complexes / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological / Q000378:metabolism / Q000503:physiopathology; D014471:Umbilical Veins / Q000166:cytology
D001672:Biocompatible Materials; D004338:Drug Combinations; D007797:Laminin; D009097:Multienzyme Complexes; D011509:Proteoglycans; D011518:Proto-Oncogene Proteins; C059485:matrigel; D003094:Collagen; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases