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Cited by 73Angiogenesis and VEGF in CancerCholesterol and Lipid MetabolismCaveolin-1 and cellular processes

Liver X Receptor Activation Reduces Angiogenesis by Impairing Lipid Raft Localization and Signaling of Vascular Endothelial Growth Factor Receptor-2

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Noghero, Alessio, Perino, Alessia, Seano, Giorgio, Saglio, Elisa, Sasso, Giuseppe Lo, Veglio, Franco, Primo, Luca, Hirsch, Emilio +2 more·2012·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.112.250621
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Abstract

Objective—: Liver X receptors (LXRα, LXRβ) are master regulators of cholesterol homeostasis. In the endothelium, perturbations of cell cholesterol have an impact on fundamental processes. We, therefore, assessed the effects of LXR activation on endothelial functions related to angiogenesis in vitro and in vivo. Methods and Results—: LXR agonists (T0901317, GW3965) blunted migration, tubulogenesis, and proliferation of human umbilical vein endothelial cells. By affecting endothelial cholesterol homeostasis, LXR activation impaired the compartmentation of vascular endothelial growth factor receptor-2 in lipid rafts/caveolae and led to defective phosphorylation and downstream signaling of vascular endothelial growth factor receptor-2 upon vascular endothelial growth factor-A stimulation. Consistently, the antiangiogenic actions of LXR agonists could be prevented by coadministration of exogenous cholesterol. LXR agonists reduced endothelial sprouting from wild-type but not from LXRα −/− /LXRβ −/− knockout aortas and blunted the vascularization of implanted angioreactors in vivo. Furthermore, T0901317 reduced the growth of Lewis lung carcinoma grafts in mice by impairing angiogenesis. Conclusion—: Pharmacological activation of endothelial LXRs reduces angiogenesis by restraining cholesterol-dependent vascular endothelial growth factor receptor-2 compartmentation and signaling. Thus, administration of LXR agonists could exert therapeutic effects in pathological conditions characterized by uncontrolled angiogenesis.

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  • Previous work demonstrated that LXR induction of ABCA1 reduces angiogenesis, presumably by decreasing lipid raft mediated stabilization of the VEGF-VEGFR complex, within vascular endothelial cells.

    “Previous work has demonstrated that LXR induction of ABCA1 reduces angiogenesis, presumably by decreasing lipid raft mediated stabilization of the VEGF-VEGFR complex, within vascular endothelial cells (56).”

    From Cholesterol efflux protein, ABCA1, supports anticancer functions of myeloid immune cells (2026) · cites this paper as [56]

    The Abstract and Discussion report that LXR activation reduces angiogenesis in endothelial cells and impairs VEGFR2 localization and signaling in lipid rafts. The Discussion also says LXR activation increases both ABCA1 and ABCG1; it does not establish that ABCA1 induction alone causes the anti-angiogenic effect or that lipid rafts stabilize a VEGF–VEGFR complex. (LLM, conf=0.86)

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Research works printed but not linked: 39

  1. Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest. 2006;116(3):607-614. on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from
  2. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996;383(6602):728-731.
  3. Joseph SB, McKilligin E, Pei L, Watson MA, Collins AR, Laffitte BA, Chen M, Noh G, Goodman J, Hagger GN, Tran J, Tippin TK, Wang X, Lusis AJ, Hsueh WA, Law RE, Collins JL, Willson TM, Tontonoz P. Synthetic LXR ligand inhibits the development of atherosclerosis in mice. Proc Natl Acad Sci U S A. 2002;99(11):7604-7609.
  4. Tangirala RK, Bischoff ED, Joseph SB, Wagner BL, Walczak R, Laffitte BA, Daige CL, Thomas D, Heyman RA, Mangelsdorf DJ, Wang X, Lusis AJ, Tontonoz P, Schulman IG. Identification of macrophage liver X receptors as inhibitors of atherosclerosis. Proc Natl Acad Sci U S A. 2002;99(18):11896-11901.
  5. Bischoff ED, Daige CL, Petrowski M, Dedman H, Pattison J, Juliano J, Li AC, Schulman IG. Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J Lipid Res. 2010;51(5):900-906.
  6. Lo Sasso G, Murzilli S, Salvatore L, D'Errico I, Petruzzelli M, Conca P, Jiang ZY, Calabresi L, Parini P, Moschetta A. Intestinal specific LXR activation stimulates reverse cholesterol transport and protects from atherosclerosis. Cell Metab. 2010;12(2):187-193.
  7. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med. 2003;9(2):213-219.
  8. Blaschke F, Leppanen O, Takata Y, Caglayan E, Liu J, Fishbein MC, Kappert K, Nakayama KI, Collins AR, Fleck E, Hsueh WA, Law RE, Bruemmer D. Liver X Receptor Agonists Suppress Vascular Smooth Muscle Cell Proliferation and Inhibit Neointima Formation in Balloon-Injured Rat Carotid Arteries. Circ Res. 2004;95(12):e110-123.
  9. Fukuchi J, Kokontis JM, Hiipakka RA, Chuu C-p, Liao S. Antiproliferative Effect of Liver X Receptor Agonists on LNCaP Human Prostate Cancer Cells. Cancer Res. 2004;64(21):7686-7689.
  10. Wente W, Brenner MB, Zitzer H, Gromada J, Efanov AM. Activation of Liver X Receptors and Retinoid X Receptors Induces Growth Arrest and Apoptosis in Insulin-Secreting Cells. Endocrinology. 2007;148(4):1843-1849. on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from
  11. Meng Z, Nie J, Ling J, Sun J, Zhu Y, Gao L, Lv J, Zhu D, Sun Y, Han X. Activation of liver X receptors inhibits pancreatic islet beta cell proliferation through cell cycle arrest. Diabetologia. 2009;52(1):125-135.
  12. Chuu C-P, Lin H-P. Antiproliferative Effect of LXR Agonists T0901317 and 22(R)- Hydroxycholesterol on Multiple Human Cancer Cell Lines. Anticancer Res. 2010;30(9):3643-3648.
  13. Pommier AJ, Alves G, Viennois E, Bernard S, Communal Y, Sion B, Marceau G, Damon C, Mouzat K, Caira F, Baron S, Lobaccaro JM. Liver X Receptor activation downregulates AKT survival signaling in lipid rafts and induces apoptosis of prostate cancer cells. Oncogene. 2010;29(18):2712-2723.
  14. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell. 2008;134(1):97-111.
  15. Lingwood D, Simons K. Lipid rafts as a membrane-organizing principle. Science. 2010;327(5961):46-50.
  16. Lo Sasso G, Celli N, Caboni M, Murzilli S, Salvatore L, Morgano A, Vacca M, Pagliani T, Parini P, Moschetta A. Down-regulation of the LXR transcriptome provides the requisite cholesterol levels to proliferating hepatocytes. Hepatology. 2009;51(4):1334-1344.
  17. Liao H, Langmann T, Schmitz G, Zhu Y. Native LDL Upregulation of ATP-Binding Cassette Transporter-1 in Human Vascular Endothelial Cells. Arterioscler Thromb Vasc Biol. 2002;22(1):127- 132.
  18. Norata GD, Ongari M, Uboldi P, Pellegatta F, Catapano AL. Liver X receptor and retinoic X receptor agonists modulate the expression of genes involved in lipid metabolism in human endothelial cells. Int J Mol Med. 2005;16(4):717-722.
  19. Morello F, Saglio E, Noghero A, Schiavone D, Williams TA, Verhovez A, Bussolino F, Veglio F, Mulatero P. LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms. Atherosclerosis. 2009;207(1):38-44. on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from
  20. Labrecque L, Royal I, Surprenant DS, Patterson C, Gingras D, Beliveau R. Regulation of vascular endothelial growth factor receptor-2 activity by caveolin-1 and plasma membrane cholesterol. Mol Biol Cell. 2003;14(1):334-347.
  21. Liao W-X, Feng L, Zhang H, Zheng J, Moore TR, Chen D-B. Compartmentalizing VEGF- Induced ERK2/1 Signaling in Placental Artery Endothelial Cell Caveolae: A Paradoxical Role of Caveolin-1 in Placental Angiogenesis in Vitro. Mol Endocrinol. 2009;23(9):1428-1444.
  22. Noghero A, Arese M, Bussolino F, Gualandris A. Mature endothelium and neurons are simultaneously derived from embryonic stem cells by 2D in vitro culture system. J Cell Mol Med. 2011;15(10):2200-2215.
  23. Peet DJ, Turley SD, Ma W, Janowski BA, Lobaccaro J-MA, Hammer RE, Mangelsdorf DJ. Cholesterol and Bile Acid Metabolism Are Impaired in Mice Lacking the Nuclear Oxysterol Receptor LXR[alpha]. Cell. 1998;93(5):693-704.
  24. Repa JJ, Turley SD, Lobaccaro J-MA, Medina J, Li L, Lustig K, Shan B, Heyman RA, Dietschy JM, Mangelsdorf DJ. Regulation of Absorption and ABC1-Mediated Efflux of Cholesterol by RXR Heterodimers. Science. 2000;289(5484):1524-1529.
  25. Primo L, Seano G, Roca C, Maione F, Gagliardi PA, Sessa R, Martinelli M, Giraudo E, di Blasio L, Bussolino F. Increased Expression of alpha6 Integrin in Endothelial Cells Unveils a Proangiogenic Role for Basement Membrane. Cancer Res. 2010;70(14):5759-5769.
  26. Cascone I, Napione L, Maniero F, Serini G, Bussolino F. Stable interaction between alpha5beta1 integrin and Tie2 tyrosine kinase receptor regulates endothelial cell response to Ang-1. J Cell Biol. 2005;170(6):993-1004.
  27. Vaisman BL, Demosky SJ, Stonik JA, Ghias M, Knapper CL, Sampson ML, Dai C, Levine SJ, Remaley AT. Endothelial expression of human ABCA1 in mice increases plasma HDL cholesterol and reduces diet-induced atherosclerosis. J Lipid Res. 2012;53(1):158-167.
  28. Rohrer L, Ohnsorg PM, Lehner M, Landolt F, Rinninger F, von Eckardstein A. High-Density Lipoprotein Transport Through Aortic Endothelial Cells Involves Scavenger Receptor BI and ATP- Binding Cassette Transporter G1. Circ Res. 2009;104(10):1142-1150. on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from
  29. Xu J, Dang Y, Ren YR, Liu JO. Cholesterol trafficking is required for mTOR activation in endothelial cells. Proc Natl Acad Sci U S A. 2010;107(10):4764-4769.
  30. Vincent L, Chen W, Hong L, Mirshahi F, Mishal Z, Mirshahi-Khorassani T, Vannier J-P, Soria J, Soria C. Inhibition of endothelial cell migration by cerivastatin, an HMG-CoA reductase inhibitor: contribution to its anti-angiogenic effect. FEBS Letters. 2001;495(3):159-166.
  31. Kim KH, Lee GY, Kim JI, Ham M, Won Lee J, Kim JB. Inhibitory effect of LXR activation on cell proliferation and cell cycle progression through lipogenic activity. J Lipid Res. 2010;51(12):3425-3433.
  32. Vedin LL, Lewandowski SA, Parini P, Gustafsson JA, Steffensen KR. The oxysterol receptor LXR inhibits proliferation of human breast cancer cells. Carcinogenesis. 2009;30(4):575-579.
  33. Walczak R, Joseph SB, Laffitte BA, Castrillo A, Pei L, Tontonoz P. Transcription of the vascular endothelial growth factor gene in macrophages is regulated by liver X receptors. J Biol Chem. 2004;279(11):9905-9911.
  34. Olsson A-K, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling -in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359-371.
  35. Vincent Lc, Soria C, Mirshahi F, Opolon P, Mishal Z, Vannier J-P, Soria J, Hong L. Cerivastatin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, Inhibits Endothelial Cell Proliferation Induced by Angiogenic Factors In Vitro and Angiogenesis in In Vivo Models. Arterioscler Thromb Vasc Biol. 2002;22(4):623-629.
  36. Panzenboeck U, Balazs Z, Sovic A, Hrzenjak A, Levak-Frank S, Wintersperger A, Malle E, Sattler W. ABCA1 and Scavenger Receptor Class B, Type I, Are Modulators of Reverse Sterol Transport at an in Vitro Blood-Brain Barrier Constituted of Porcine Brain Capillary Endothelial Cells. J Biol Chem. 2002;277(45):42781-42789.
  37. Zelcer N, Hong C, Boyadjian R, Tontonoz P. LXR Regulates Cholesterol Uptake Through Idol-Dependent Ubiquitination of the LDL Receptor. Science. 2009;325(5936):100-104.
  38. Sonveaux P, Martinive P, DeWever J, Batova Z, Daneau Gr, Pelat M, Ghisdal P, Grégoire V, Dessy C, Balligand J-L, Feron O. Caveolin-1 Expression Is Critical for Vascular Endothelial Growth on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from n=20. (G-I) Distribution of VEGFR2, flotillin-2 (Flot-2), caveolin-1 (Cav-1) and binding immunoglobulin protein (BiP) in the protein fractions obtained from HUVEC (ultracentrifugation on a discontinuous sucrose gradient) treated as in D. The lipid raft compartment is represented in the lighter fractions (1-3), while the endoplasmic reticulum peaks in the heavier fractions (7-10). Representative blots of 3 experiments. Figure 5. LXR activation impairs angiogenesis in mouse tissues. (A) Endothelial sprouting from mouse aortic rings incubated with the indicated compounds for 5 days: vehicle (DMSO), GW3965 (10
  39. LXR activation reduces tumor angiogenesis. (A) Protein levels of ABCA1, ABCG1, LDLR in HUVEC and LLC-1 cells treated for 18 hours with vehicle (DMSO) or T0901317 (T090, 1 μM). Representative blots of 3 experiments. (B) Growth curve of LLC-1 tumor grafts in mice treated with vehicle (CMC-Tween 20) or T0901317 (20 mg/kg i.p. q.d.) for one week. Tumor volume was calculated based on daily caliper measurements. *p<0.05, **p<0.01, n=10 mice per group. (C) ABCA1/CD31 immunostaining in tumor vessels. Treatments were performed as in B. Left: representative images (red: ABCA1, green: CD31, blue: DAPI), 40x magnification, scale bar 30 μm. Right: quantification of ABCA1 fluorescence in CD31+ areas. **p<0.01, n=10 per group. (D) CD31 immunostaining in tumor sections. Treatments were performed as in B. Left: representative images, 10x magnification, scale bar 100 μm (green: CD31, blue: DAPI). Right: quantification of CD31 immunofluorescence (% of tumor area). **p<0.01, n=10 per group. on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded from on May 20, 2012 http://submit-atvb.ahajournals.org ATVB/2012/250621, Original Contribution, Downloaded

Cited by

Sorted by citations

Authors
Noghero, A., Perino, A., Seano, G., Saglio, E., Sasso, G. L., Veglio, F., Primo, L., Hirsch, E., Bussolino, F., & Morello, F.
Affiliations
Azienda Ospedaliero Universitaria San Giovanni Battista (IT)
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2012-09
Volume
32
Issue
9
Pages
2280-2288
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.112.250621
OpenAlex
W2033303602
Cited by
73
References
0
Citations by year
2026: 1 · 2025: 5 · 2024: 3 · 2023: 3 · 2022: 7 · 2021: 7 · 2020: 9 · 2019: 6 · 2018: 6 · 2017: 6 · 2016: 5 · 2015: 4 · 2014: 5 · 2013: 6
FWCI
1.92
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
  • PubMed (publishedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
Funders
  • Fondazione CRT
  • Associazione Italiana per la Ricerca sul Cancro
  • Regione Piemonte
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Caveolin-1 and cellular processes
Keywords
liver X receptor, angiogenesis, vascular endothelial growth factor receptor 2, lipid rafts, caveolae, LXR agonists, T0901317, GW3965, endothelial cell migration, tubulogenesis, VEGF-A signaling, tumor angiogenesis, Lewis lung carcinoma, aortic endothelium
MeSH terms
Liver X Receptors, Benzenesulfonamides, Animals, Aorta, Thoracic, Benzoates, Benzylamines, Cell Movement, Cells, Cultured, Cholesterol, Female, Fluorocarbons, Humans, Hydrocarbons, Fluorinated, Mice, Inbred C57BL, Phosphorylation, Sulfonamides, Time Factors, Transfection, Signal Transduction, Mice, Knockout, Carcinoma, Lewis Lung, Neovascularization, Physiologic, Angiogenesis Inhibitors, Membrane Microdomains, RNA Interference, Vascular Endothelial Growth Factor Receptor-2, Vascular Endothelial Growth Factor A, Endothelial Cells, Tumor Burden, Cell Proliferation, Mice, Orphan Nuclear Receptors, Human Umbilical Vein Endothelial Cells

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