VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1
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...
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| Format: | Article |
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MDPI AG
2020-03-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/3/687 |
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| author | Katrin Spengler Nderim Kryeziu Silke Große Alexander S. Mosig Regine Heller |
| author_facet | Katrin Spengler Nderim Kryeziu Silke Große Alexander S. Mosig Regine Heller |
| author_sort | Katrin Spengler |
| collection | DOAJ |
| description | 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 AMPKα1-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. |
| first_indexed | 2024-03-12T07:43:58Z |
| format | Article |
| id | doaj.art-cc6ab4b2c814429cb597f5d2e8ccff0c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T07:43:58Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-cc6ab4b2c814429cb597f5d2e8ccff0c2023-09-02T21:06:06ZengMDPI AGCells2073-44092020-03-019368710.3390/cells9030687cells9030687VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1Katrin Spengler0Nderim Kryeziu1Silke Große2Alexander S. Mosig3Regine Heller4Institute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, GermanyInstitute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, GermanyInstitute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, GermanyInstitute of Biochemistry II and Center for Sepsis Control and Care, Jena University Hospital, 07743 Jena, GermanyInstitute of Molecular Cell Biology, Center for Molecular Biomedicine, Jena University Hospital, 07743 Jena, GermanyAMP-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 AMPKα1-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.https://www.mdpi.com/2073-4409/9/3/687ampkautophagyangiogenesisvegfmtorulk1 |
| spellingShingle | Katrin Spengler Nderim Kryeziu Silke Große Alexander S. Mosig Regine Heller VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1 Cells ampk autophagy angiogenesis vegf mtor ulk1 |
| title | VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1 |
| title_full | VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1 |
| title_fullStr | VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1 |
| title_full_unstemmed | VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1 |
| title_short | VEGF Triggers Transient Induction of Autophagy in Endothelial Cells via AMPKα1 |
| title_sort | vegf triggers transient induction of autophagy in endothelial cells via ampkα1 |
| topic | ampk autophagy angiogenesis vegf mtor ulk1 |
| url | https://www.mdpi.com/2073-4409/9/3/687 |
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