PMID- 32168879
OWN - NLM
STAT- MEDLINE
DCOM- 20210311
LR  - 20211204
IS  - 2073-4409 (Electronic)
IS  - 2073-4409 (Linking)
VI  - 9
IP  - 3
DP  - 2020 Mar 11
TI  - VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKalpha1.
LID - 10.3390/cells9030687 [doi]
LID - 687
AB  - AMP-activated protein kinase (AMPK) is activated by vascular endothelial growth 
      factor (VEGF) in endothelial cells and it is significantly involved in 
      VEGF-induced angiogenesis. This study investigates whether the VEGF/AMPK pathway 
      regulates autophagy in endothelial cells and whether this is linked to its 
      pro-angiogenic role. We show that VEGF leads to AMPKalpha1-dependent phosphorylation 
      of Unc-51-like kinase 1 (ULK1) at its serine residue 556 and to the subsequent 
      phosphorylation of the ULK1 substrate ATG14. This triggers initiation of 
      autophagy as shown by phosphorylation of ATG16L1 and conjugation of the 
      microtubule-associated protein light chain 3B, which indicates autophagosome 
      formation; this is followed by increased autophagic flux measured in the presence 
      of bafilomycin A1 and by reduced expression of the autophagy substrate p62. 
      VEGF-induced autophagy is transient and probably terminated by mechanistic target 
      of rapamycin (mTOR), which is activated by VEGF in a delayed manner. We show that 
      functional autophagy is required for VEGF-induced angiogenesis and may have 
      specific functions in addition to maintaining homeostasis. In line with this, 
      inhibition of autophagy impaired VEGF-mediated formation of the Notch 
      intracellular domain, a critical regulator of angiogenesis. Our study 
      characterizes autophagy induction as a pro-angiogenic function of the VEGF/AMPK 
      pathway and suggests that timely activation of autophagy-initiating pathways may 
      help to initiate angiogenesis.
FAU - Spengler, Katrin
AU  - Spengler K
AD  - Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena 
      University Hospital, 07743 Jena, Germany.
FAU - Kryeziu, Nderim
AU  - Kryeziu N
AD  - Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena 
      University Hospital, 07743 Jena, Germany.
FAU - Grosse, Silke
AU  - Grosse S
AD  - Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena 
      University Hospital, 07743 Jena, Germany.
FAU - Mosig, Alexander S
AU  - Mosig AS
AD  - Institute of Biochemistry II and Center for Sepsis Control and Care, Jena 
      University Hospital, 07743 Jena, Germany.
FAU - Heller, Regine
AU  - Heller R
AD  - Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena 
      University Hospital, 07743 Jena, Germany.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200311
PL  - Switzerland
TA  - Cells
JT  - Cells
JID - 101600052
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (VEGFA protein, human)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog)
RN  - EC 2.7.11.1 (ULK1 protein, human)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 2.7.11.31 (PRKAA1 protein, human)
SB  - IM
MH  - AMP-Activated Protein Kinases/*metabolism
MH  - Autophagy/physiology
MH  - Autophagy-Related Protein-1 Homolog/metabolism
MH  - Endothelial Cells/cytology/*metabolism
MH  - Human Umbilical Vein Endothelial Cells
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins/metabolism
MH  - Phosphorylation
MH  - Transfection
MH  - Vascular Endothelial Growth Factor A/*metabolism
PMC - PMC7140637
OTO - NOTNLM
OT  - AMPK
OT  - ULK1
OT  - VEGF
OT  - angiogenesis
OT  - autophagy
OT  - mTOR
COIS- The authors declare no conflict of interest.
EDAT- 2020/03/15 06:00
MHDA- 2021/03/12 06:00
PMCR- 2020/03/01
CRDT- 2020/03/15 06:00
PHST- 2020/01/31 00:00 [received]
PHST- 2020/03/03 00:00 [revised]
PHST- 2020/03/10 00:00 [accepted]
PHST- 2020/03/15 06:00 [entrez]
PHST- 2020/03/15 06:00 [pubmed]
PHST- 2021/03/12 06:00 [medline]
PHST- 2020/03/01 00:00 [pmc-release]
AID - cells9030687 [pii]
AID - cells-09-00687 [pii]
AID - 10.3390/cells9030687 [doi]
PST - epublish
SO  - Cells. 2020 Mar 11;9(3):687. doi: 10.3390/cells9030687.