Cited by 332Angiogenesis and VEGF in CancerMetabolism, Diabetes, and CancerCancer, Hypoxia, and Metabolism

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AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

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Nagata, Daisuke, Mogi, Masaki, Walsh, Kenneth·2003·Journal of Biological Chemistry

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Abstract

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.

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Background
Effect of metformin on the proliferation, migration, and MMP-2 and-9 expression of human umbilical vein endothelial cells
ESFAHANIAN, N., SHAKIBA, Y., NIKBIN, B., SORAYA, H., MALEKI-DIZAJI, N., GHAZI-KHANSARI, M., & GARJANI, A. (2012) · Molecular Medicine Reports · doi:10.3892/mmr.2012.753 · Cited by 120
“Furthermore, it has been reported that the activation of AMPK signaling in endothelial cells is essential for angiogenesis under hypoxic conditions (32), but not in normoxia.”
Background
Modulation of endothelium function by fatty acids
Mallick, R., & Duttaroy, A. K. (2021) · Molecular and Cellular Biochemistry · doi:10.1007/s11010-021-04260-9 · Cited by 129
“1 3 metabolic sensor mammalian targets of rapamycin complex 1 to promote endothelial cell migration and angiogenesis [231, 232].”
Background
Regulation of NAD(P)H oxidases by AMPK in cardiovascular systems
Song, P., & Zou, M. (2012) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2012.01.025 · Cited by 122
Oxygen and glucose deprivation induces widespread alterations in mRNA translation within 20 minutes
Andreev, D. E., O’Connor, P. B. F., Zhdanov, A. V., Dmitriev, R. I., Shatsky, I. N., Papkovsky, D. B., & Baranov, P. V. (2015) · Genome biology · doi:10.1186/s13059-015-0651-z · Cited by 111
“AMPK is an important sensor of energy starvation and adaptive response to ischemia in mammalian cells [9,10].”
Background
AMP‐ACTIVATED PROTEIN KINASE ACTIVATION AS A STRATEGY FOR PROTECTING VASCULAR ENDOTHELIAL FUNCTION
Zou, M., & Wu, Y. (2007) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/j.1440-1681.2007.04851.x · Cited by 116
“physiological functions; for example, it is essential for angiogenesis in response to hypoxic stress.(44) The functional significance of these different combinations remains unclear; however, it is noted that AMPK complexes containing the a1 isoform are less sensitive to AMP.”
Background
Epoxyeicosatrienoic acids are part of the VEGF-activated signaling cascade leading to angiogenesis
Webler, A. C., Michaelis, U. R., Popp, R., Barbosa‐Sicard, E., Murugan, A., Falck, J. R., Fißlthaler, B., & Fleming, I. (2008) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00230.2008 · Cited by 115
“In the search to identify the molecular mechanism(s) underlying the VEGF-induced increase in CYP2C expression, we analyzed the role of the AMPK as VEGF has previously been demonstrated to activate the kinase in endothelial cells (36), and activation of AMPK has been linked to endothelial cell migration and angiogenesi…”
Background
AMPK-Dependent Metabolic Regulation by PPAR Agonists
Lee, W. H., & Kim, S. G. (2010) · PPAR Research · doi:10.1155/2010/549101 · Cited by 117
“Since AMPK responds to external stress and regulate cellular homeostasis, its activation enables endothelial cells to survive against severe stress [53, 54].”
Background
Estradiol-Mediated Endothelial Nitric Oxide Synthase Association With Heat Shock Protein 90 Requires Adenosine Monophosphate-Dependent Protein Kinase
Schulz, E., Anter, E., Zou, M., & Keaney, J. F. (2005) · Circulation · doi:10.1161/circulationaha.105.546812 · Cited by 114
Protein Modification by O-Linked GlcNAc Reduces Angiogenesis by Inhibiting Akt Activity in Endothelial Cells
Luo, B., Soesanto, Y., & McClain, D. A. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.107.159533 · Cited by 112
Protective Roles of Endothelial AMP-Activated Protein Kinase Against Hypoxia-Induced Pulmonary Hypertension in Mice
Omura, J., Satoh, K., Kikuchi, N., Satoh, T., Kurosawa, R., Nogi, M., Otsuki, T., Kozu, K., Numano, K., Suzuki, K., et al. (2016) · Circulation Research · doi:10.1161/circresaha.115.308178 · Cited by 110
“These data are consistent with the previous study demonstrating that endothelial AMPK is essential for endothelial function and vascular homeostasis, especially in hypoxia.(41) Indeed, activation of eNOS catalyzes the production of NO, which is a crucial molecule for the maintenance of endothelial function and vascula…”
Result
AMPK and vasculoprotection
Ewart, M., & Kennedy, S. (2010) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2010.11.002 · Cited by 112
Integrin-Linked Kinase, a Hypoxia-Responsive Molecule, Controls Postnatal Vasculogenesis by Recruitment of Endothelial Progenitor Cells to Ischemic Tissue
Lee, S., Youn, S., Cho, H., Li, L., Kim, T.-Y., Yook, H.-S., Chung, J.-W., Hur, J., Yoon, C., Park, K. W., et al. (2006) · Circulation · doi:10.1161/circulationaha.105.595918 · Cited by 108
Altered Metabolism and Persistent Starvation Behaviors Caused by Reduced AMPK Function in Drosophila
Johnson, E. C., Kazgan, N., Bretz, C. A., Forsberg, L. J., Hector, C. E., Worthen, R. J., Onyenwoke, R. U., & Brenman, J. E. (2010) · PLoS ONE · doi:10.1371/journal.pone.0012799 · Cited by 105
“For example, the neuroendocrine cells that produce the Adipokinetic Hormone (AKH) are critical for the formation of starvation-induced hyperactive behaviors [19–20].”
Background
Skeletal Muscle Capillarity during Hypoxia: VEGF and Its Activation
Breen, E. C., Tang, K., Olfert, M., Knapp, A. E., & Wagner, P. D. (2008) · High Altitude Medicine & Biology · doi:10.1089/ham.2008.1010 · Cited by 103
“Further, using subcutaneous implanted matrigel plugs as an in vivo model, a dominant negative AMPK has been demonstrated to inhibit angiogenesis (Nagata et al., 2003).”
Adaptation to oxygen deprivation in cultures of human pluripotent stem cells, endothelial progenitor cells, and umbilical vein endothelial cells
Abaci, H. E., Truitt, R., Luong, E., Drazer, G., & Gerecht, S. (2010) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00484.2009 · Cited by 108
Salidroside improves endothelial function and alleviates atherosclerosis by activating a mitochondria-related AMPK/PI3K/Akt/eNOS pathway
Xing, S.-S., Yang, X.-Y., Zheng, T., Li, W.-J., Wu, D., Chi, J.-Y., Bian, F., Bai, X.-L., Wu, G.-J., Zhang, Y.-Z., et al. (2015) · Vascular Pharmacology · doi:10.1016/j.vph.2015.07.004 · Cited by 99
Identification of the Serine 307 of LKB1 as a Novel Phosphorylation Site Essential for Its Nucleocytoplasmic Transport and Endothelial Cell Angiogenesis
Xie, Z., Dong, Y., Zhang, J., Scholz, R., Neumann, D., & Zou, M. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.01417-08 · Cited by 102
Activation of AMP-activated Protein Kinase by Vascular Endothelial Growth Factor Mediates Endothelial Angiogenesis Independently of Nitric-oxide Synthase
Stahmann, N., Woods, A., Spengler, K., Heslegrave, A., Bauer, R., Krause, S., Viollet, B., Carling, D., & Heller, R. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.108688 · Cited by 100
Interplay Between Reactive Oxygen/Reactive Nitrogen Species and Metabolism in Vascular Biology and Disease
Ushio‐Fukai, M., Ash, D., Nagarkoti, S., de Chantemèle, E. J. B., Fulton, D. J., & Fukai, T. (2021) · Antioxidants and Redox Signaling · doi:10.1089/ars.2020.8161 · Cited by 99
“AMPK also protects against atherosclerosis (201, 244, 311, 374, 376).”
Cardiovascular and metabolic effects of Berberine
Affuso, F. (2010) · World Journal of Cardiology · doi:10.4330/wjc.v2.i4.71 · Cited by 94
The prokineticin receptor‐1 (GPR73) promotes cardiomyocyte survival and angiogenesis
Urayama, K., Guilini, C., Messaddeq, N., Hu, K., Steenman, M., Kurose, H., Ert, G., & Nebigil, C. G. (2007) · The FASEB Journal · doi:10.1096/fj.07-8116com · Cited by 94
“Twenty-four-well culture plates were coated with Matrigel (BD Biosciences, Bedford, MA, USA) according to the manufacturer’s instructions and as described previously (24).”
Method
Anti-Angiogenic Properties of Ginsenoside Rg3
Nakhjavani, M., Smith, E., Townsend, A. R., Price, T. J., & Hardingham, J. E. (2020) · Molecules · doi:10.3390/molecules25214905 · Cited by 93
“The other activator of eNOS is AMP-activated protein kinase (AMPK) (Figure 2a), which is a stress activated kinase.”
BackgroundInfluential
AMP-activated protein kinase mediates VEGF-stimulated endothelial NO production
Reihill, J. A., Ewart, M., Hardie, D. G., & Salt, I. P. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.01.110 · Cited by 91
“AMPK is activated by phosphorylation at Thr172 by at least two recently characterised upstream kinases, LKB1 and Ca2+/calmodulin-dependent protein kinase kinase (CaMKK), especially the b isoform [10–13].”
Influential
AMP-activated Protein Kinase in the Control of Cardiac Metabolism and Remodeling
Horman, S., Beauloye, C., Vanoverschelde, J., & Bertrand, L. (2012) · Current Heart Failure Reports · doi:10.1007/s11897-012-0102-z · Cited by 93
“This activation loop is critical as dominant-negative AMPK abrogates both endothelial cell migration as well as in vitro differentiation into tubelike structures under hypoxic conditions [86].”
Background
The Homeobox Gene Gax Inhibits Angiogenesis through Inhibition of Nuclear Factor-κB–Dependent Endothelial Cell Gene Expression
Patel, S., Leal, A. D., & Gorski, D. H. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-3431 · Cited by 93
“in mice, can stimulate the ingrowth of blood vessels into the Matrigel plug from the surrounding tissue, allowing in vivo tumor cell-free estimates of angiogenesis (24).”
Influential
Angiogenesis Impairment in Diabetes: Role of Methylglyoxal-Induced Receptor for Advanced Glycation Endproducts, Autophagy and Vascular Endothelial Growth Factor Receptor 2
Liu, H., Yu, S., Zhang, H., & Xu, J. (2012) · PLoS ONE · doi:10.1371/journal.pone.0046720 · Cited by 95
“The tube or vascular-like structure formation by endothelial cells was assessed on growth factor-reduced Matrigel (BD Biosciences), as described [39].”
Retracted
Evidence of cancer‐promoting roles for AMPK and related kinases
Monteverde, T., Muthalagu, N., Port, J., & Murphy, D. J. (2015) · FEBS Journal · doi:10.1111/febs.13534 · Cited by 91
“Notably, AMPK is activated by hypoxia in a ROS-dependent manner [19] and is implicated in hypoxiadriven angiogenesis [20].”
Background
Metabolic activation of AMP kinase in vascular smooth muscle
Rubin, L. J., Magliola, L., Feng, X., JONES, A. W., & Hale, C. C. (2004) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00075.2004 · Cited by 90
“Chronic activation of AMPK ( 12 h) by hypoxia, however, was required to initiate angiogenic changes (26).”
Background
Exercise prevents the adverse effects of maternal obesity on placental vascularization and fetal growth
Son, J. S., Liu, X., Tian, Q., Zhao, L., Chen, Y., Hu, Y., Chae, S. A., de Avila, J. M., Zhu, M. J., & Du, ‬. (2019) · The Journal of Physiology · doi:10.1113/jp277698 · Cited by 86
“In alignment, AMPK knockdown inhibited placental nutrient transport function (Carey et al. 2014) and AMPK signalling was reported to be essential for hypoxia-induced angiogenesis in endothelial cells (Nagata et al. 2003).”
Background
High-fat diet induces endothelial dysfunction through a down-regulation of the endothelial AMPK-PI3K-Akt-eNOS pathway
García‐Prieto, C. F., Hernández-Nuño, F., Rio, D. D., Ruiz‐Hurtado, G., Aránguez, I., Ruiz‐Gayo, M., Somoza, B., & Fernández‐Alfonso, M. S. (2014) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201400539 · Cited by 86
Muscle-derived follistatin-like 1 functions to reduce neointimal formation after vascular injury
Miyabe, M., Ohashi, K., Shibata, R., Uemura, Y., Ogura, Y., Yuasa, D., Kambara, T., Kataoka, Y., Yamamoto, T., Matsuo, K., et al. (2014) · Cardiovascular Research · doi:10.1093/cvr/cvu105 · Cited by 87
Adiponectin Promotes Revascularization of Ischemic Muscle through a Cyclooxygenase 2-Dependent Mechanism
Ohashi, K., Ouchi, N., Sato, K., Higuchi, A., Ishikawa, T., Herschman, H. R., Kihara, S., & Walsh, K. X. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00126-09 · Cited by 83
“dominant-negative Akt (Ad-dnAkt), or -galactosidase (Ad- gal) at a multiplicity of infection of 50 for 24 h (31, 39, 46).”
Background
Exosomal EPHA2 derived from highly metastatic breast cancer cells promotes angiogenesis by activating the AMPK signaling pathway through Ephrin A1-EPHA2 forward signaling
Han, B., Zhang, H., Tian, R., Liu, H., Wang, Z., Wang, Z., Tian, J., Cui, Y., Ren, S., Zuo, X., et al. (2022) · Theranostics · doi:10.7150/thno.72404 · Cited by 84
“AMPK activation can upregulate the expression of pro-angiogenic factors such as HIF-1α to promote angiogenesis and improve local blood supply and oxygenation in cardiovascular and cerebrovascular disease models [27, 53].”
Background
Disturbed Cross Talk between Insulin-Like Growth Factor I and AMP-Activated Protein Kinase as a Possible Cause of Vascular Dysfunction in the Amyloid Precursor Protein/Presenilin 2 Mouse Model of Alzheimer's Disease
Lopez‐Lopez, C., Dietrich, M. O., Metzger, F., Loetscher, H., & Torres‐Alemán, I. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4345-06.2007 · Cited by 83
“AMPK is involved in angiogenesis (Nagata et al., 2003) and regulates insulin/IGF-I signaling in cancer cells (Kim et al., 2001; Suzuki et al., 2004).”
BackgroundInfluential
AMP-activated protein kinase conducts the ischemic stress response orchestra
Young, L. H. (2008) · Circulation · doi:10.1161/circulationaha.107.713115 · Cited by 82
Aquaporin 1 is required for hypoxia-inducible angiogenesis in human retinal vascular endothelial cells
Kaneko, K., Yagui, K., Tanaka, A., Yoshihara, K., Ishikawa, K., Takahashi, K., Bujo, H., Sakurai, K., & Saitō, Y. (2008) · Microvascular Research · doi:10.1016/j.mvr.2007.12.003 · Cited by 82
ICAM-1–mediated Endothelial Nitric Oxide Synthase Activation via Calcium and AMP-activated Protein Kinase Is Required for Transendothelial Lymphocyte Migration
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Cytokines in Stress
Giannantonio, M. D., Frydas, S., Kempuraj, D., Karagouni, E., Hatzistilianou, M. N., Conti, C. M., Boucher, W. S., Papadopoulou, N., Donelan, J., Cao, J., et al. (2005) · International Journal of Immunopathology and Pharmacology · doi:10.1177/039463200501800101 · Cited by 82
Mechanism and Role of High Density Lipoprotein-induced Activation of AMP-activated Protein Kinase in Endothelial Cells
Kimura, T., Tomura, H., Sato, K., Ito, M., Matsuoka, I., Im, D., Kuwabara, A., Mogi, C., Itoh, H., Kurose, H., et al. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.043869 · Cited by 81
The role of AMP-activated protein kinase in the cardiovascular system
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Authors: Nagata, D., Mogi, M., & Walsh, K.
Affiliations: Boston University (US)
Corresponding author: Walsh, Kenneth
ORCID: Nagata, Daisuke
Mogi, Masaki
Walsh, Kenneth
Venue: Journal of Biological Chemistry
Publisher: Elsevier BV
Published: 2003-08
Volume: 278
Issue: 33
Pages: 31000-31006
ISSN: 0021-9258 (ISSN-L)
DOI: 10.1074/jbc.m300643200
OpenAlex: W2070475419
Cited by: 331
References: 58
Citations by year: 2026: 3 · 2025: 2 · 2024: 7 · 2023: 6 · 2022: 9 · 2021: 14 · 2020: 18 · 2019: 12 · 2018: 14 · 2017: 11 · 2016: 8 · 2015: 20 · 2014: 24 · 2013: 14 · 2012: 22
FWCI: 5.53
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
creativecommons.org/licenses/by/4.0/ (vor, 6270 d)
Locations: Journal of Biological Chemistry (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Japan Heart Foundation
National Institutes of Health (AG17241, AR40197, AG15052)
National Institute on Aging (AG17241, AG15052, R01AG017241)
National Heart, Lung, and Blood Institute (HL-66957, P01HL066957)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR-40197, R01AR040197)
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
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Keywords: AMPK, AMPK signaling, angiogenesis, hypoxia, endothelial cells, human umbilical vein endothelial cells, Akt signaling, endothelial cell migration, tube formation, vascular endothelial growth factor, ischemia
MeSH terms: Hypoxia, Biocompatible Materials, Capillaries, Cell Movement, Cells, Cultured, Collagen, Drug Combinations, Endothelium, Vascular, Humans, Laminin, Multienzyme Complexes, Proteoglycans, Proto-Oncogene Proteins, Stress, Physiological, Umbilical Veins, Signal Transduction, Protein Serine-Threonine Kinases, Neovascularization, Physiologic, Proto-Oncogene Proteins c-akt, AMP-Activated Protein Kinases

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AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

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