Impaired Expression of Uncoupling Protein 2 Causes Defective Postischemic Angiogenesis in Mice Deficient in AMP-Activated Protein Kinase α Subunits
Open accessAbstract
OBJECTIVE: The aim of the present study was to determine whether mitochondrial uncoupling protein (UCP) 2 is required for AMPK-dependent angiogenesis in ischemia in vivo. METHODS AND RESULTS: Angiogenesis was assayed by monitoring endothelial tube formation (a surrogate for angiogenesis) in human umbilical vein endothelial cells (ECs), isolated mouse aortic endothelial cells (MAECs), and pulmonary microvascular endothelial cells or in ischemic thigh adductor muscles from wild-type (WT) mice or mice deficient in either AMPKα1 or AMPKα2. AMPK inhibition with pharmacological inhibitor (compound C) or genetic means (transfection of AMPKα-specific small interfering RNA) significantly lowered the tube formation in human umbilical vein ECs. Consistently, compared with WT mice, tube formation in MAECs isolated from either AMPKα1(-/-) or AMPKα2(-/-) mice, which exhibited oxidative stress and reduced expression of UCP2, was significantly impaired. In addition, adenoviral overexpression of UCP2, but not adenoviruses encoding green fluorescent protein, normalized tube formation in MAECs from either AMPKα1(-/-) or AMPKα2(-/-) mice. Similarly, supplementation with sodium nitroprusside, a nitric oxide (NO) donor, restored tube formation. Furthermore, ischemia significantly increased angiogenesis, serine 1177 phosphorylation of endothelial NO synthase, and UCP2 in ischemic thigh adductor muscles from WT mice but not in those from either AMPKα1(-/-) or AMPKα2(-/-) mice. CONCLUSIONS: We conclude that AMPK-dependent UCP2 expression in ECs promotes angiogenesis in vivo.
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Impairment of tube formation in AMPKα1−/− or AMPKα2−/− cells could be normalized by adenoviral overexpression of UCP2.
“Further, the impairment of tube formation in AMPKα1−/− or AMPKα2−/− cells could be normalized by adenoviral overexpression of UCP2 [132].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [132]
Administration of NO donor sodium nitroprusside restored tube formation in both AMPKα1−/− and AMPKα2−/− mice.
“Alternatively, administration of NO donor, sodium nitroprusside, restored the tube formation in both AMPKα1−/− and AMPKα2−/− mice [132].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [132]
In endothelial cells, AMPK-dependent UCP2 expression together with eNOS phosphorylation promotes angiogenesis.
“Collectively, these results concluded that, in ECs, AMPK-dependent UCP2 expression together with eNOS phosphorylation promotes angiogenesis [132].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [132]
Inhibition of AMPK by either pharmacological inhibitor compound C or gene silencing significantly reduced tube formation in HUVECs.
“Study showed that inhibition of AMPK by either pharmacological inhibitor compound C or gene silencing significantly reduced tube formation in HUVECs [132].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [132]
Ischemia-induced ser1177 phosphorylation of eNOS in thigh adductor muscles was blocked in both AMPKα1−/− and AMPKα2−/− mice.
“In comparison with WT mice, the ischemia-induced ser1177 phosphorylation of eNOS in thigh adductor muscles was blocked in both AMPKα1−/− and AMPKα2−/− mice [132].”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [132]
Tube formation in mouse arterial endothelial cells isolated from either AMPKα1−/− or AMPKα2−/− mice was significantly impaired, exhibiting oxidative stress and reduced expression of UCP2.
“Similarly, in comparison with the WT cells, tube formation in mouse arterial endothelial cells isolated from either AMPKα1−/− or AMPKα2−/− mice was significantly impaired, exhibiting oxidative stress and reduced expression of UCP2.”
From AMPK, Mitochondrial Function, and Cardiovascular Disease (2020) · cites this paper as [132]
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AMPK, Mitochondrial Function, and Cardiovascular Disease
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Self-citation
- Authors
- Xu, M.-J., Song, P., Shirwany, N., Liang, B., Xing, J., Viollet, B., Wang, X., Zhu, Y., & Zou, M.-H.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- From the Section of Molecular Medicine, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK (M.-J.X., P.S., N.S., B.L., J.X., M.-H.Z.); Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China (M.-J.X., X.W., Y.Z.); Institut Cochin, Université Paris Descartes, CNRS (UMR 8104), Paris, France (B.V.); Institut National de la Santé et de la Recherche Médicale, U1016 and U567, Paris, France (B.V.).
- Venue
- Arteriosclerosis Thrombosis and Vascular Biology
- Published
- 2011-08
- Volume
- 31
- Issue
- 8
- Pages
- 1757-1765
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC3158995
- OpenAlex
- W2138517329
- Cited by
- 39
- References
- 44
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 4 · 2013: 4 · 2012: 5
- FWCI
- 1.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL-105157, R44HL110448, HL-110448, R01HL105157, HL 079584, R01HL079584, HL-080499, HL096032, HL074399, R01HL074399, R01HL080499, HL-089920, R43HL110448, R01HL110488, R01HL089920, R01HL096032)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- UCP2, AMPK, AMPKα1, AMPKα2, angiogenesis, endothelial tube formation, mitochondrial uncoupling, oxidative stress, endothelial nitric oxide synthase, nitric oxide, skeletal muscle ischemia, endothelial cells
- MeSH terms
- Uncoupling Protein 2, Animals, Cells, Cultured, Humans, Ion Channels, Ischemia, Male, Membrane Proteins, Mice, Inbred C57BL, Nitroprusside, Phosphoproteins, Phosphorylation, Signal Transduction, Gene Expression, Mice, Knockout, Neovascularization, Physiologic, Nitric Oxide Donors, Gene Silencing, Mitochondrial Proteins, Reactive Nitrogen Species, RNA, Small Interfering, Endothelial Cells, Mice, Nitric Oxide Synthase Type III, AMP-Activated Protein Kinases
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