{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T10:21:15Z","timestamp":1790418075002,"version":"4.1.0"},"reference-count":54,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T00:00:00Z","timestamp":1616544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002915","name":"Fondation pour la Recherche M\u00e9dicale","doi-asserted-by":"publisher","award":["EQU202003010517"],"award-info":[{"award-number":["EQU202003010517"]}],"id":[{"id":"10.13039\/501100002915","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Non-alcoholic fatty liver disease (NAFLD) has become the leading cause of chronic liver disease, exposing to the risk of liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Angio-genesis is a complex process leading to the development of new vessels from pre-existing vessels. Angiogenesis is triggered by hypoxia and inflammation and is driven by the action of proangiogenic cytokines, mainly vascular endothelial growth factor (VEGF). In this review, we focus on liver angiogenesis associated with NAFLD and analyze the evidence of liver angiogenesis in animal models of NAFLD and in NAFLD patients. We also report the data explaining the role of angiogenesis in the progression of NAFLD and discuss the potential of targeting angiogenesis, notably VEGF, to treat NAFLD.<\/jats:p>","DOI":"10.3390\/jcm10071338","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T15:42:19Z","timestamp":1616600539000},"page":"1338","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Role of Angiogenesis in the Pathogenesis of NAFLD"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5740-1508","authenticated-orcid":false,"given":"Lin","family":"Lei","sequence":"first","affiliation":[{"name":"Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universit\u00e9, INSERM, 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0033-3070","authenticated-orcid":false,"given":"Haquima","family":"EI Mourabit","sequence":"additional","affiliation":[{"name":"Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universit\u00e9, INSERM, 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Housset","sequence":"additional","affiliation":[{"name":"Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universit\u00e9, INSERM, 75012 Paris, France"},{"name":"Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR, MIVB-H), Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Saint-Antoine Hospital, 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4283-6864","authenticated-orcid":false,"given":"Axelle","family":"Cadoret","sequence":"additional","affiliation":[{"name":"Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universit\u00e9, INSERM, 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6947-2709","authenticated-orcid":false,"given":"Sara","family":"Lemoinne","sequence":"additional","affiliation":[{"name":"Centre de Recherche Saint-Antoine (CRSA) and Institute of Cardiometabolism and Nutrition (ICAN), Sorbonne Universit\u00e9, INSERM, 75012 Paris, France"},{"name":"Department of Hepatology, Reference Center for Inflammatory Biliary Diseases and Autoimmune Hepatitis (CRMR, MIVB-H), Assistance Publique-H\u00f4pitaux de Paris (AP-HP), Saint-Antoine Hospital, 75012 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/nrgastro.2017.109","article-title":"Global burden of NAFLD and NASH: Trends, predictions, risk factors and prevention","volume":"15","author":"Younossi","year":"2018","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4317","DOI":"10.1200\/JCO.20.02672","article-title":"Systemic Therapy for Advanced Hepatocellular Carcinoma: ASCO Guideline","volume":"38","author":"Gordan","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_3","first-page":"298","article-title":"Molecular mechanisms and clinical applications of angiogenesis","volume":"473","author":"Carmeliet","year":"2011","journal-title":"Nat. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1111\/j.1478-3231.2010.02369.x","article-title":"Angiogenesis in chronic liver disease and its complications","volume":"31","author":"Coulon","year":"2010","journal-title":"Liver Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2279","DOI":"10.1007\/s11033-020-05290-0","article-title":"Neovascularization is a key feature of liver fibrosis progression: Anti-angiogenesis as an innovative way of liver fibrosis treatment","volume":"47","author":"Zadorozhna","year":"2020","journal-title":"Mol. Biol. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s00441-016-2443-5","article-title":"Portal myofibroblasts connect angiogenesis and fibrosis in liver","volume":"365","author":"Lemoinne","year":"2016","journal-title":"Cell Tissue Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.jhep.2016.07.009","article-title":"Liver sinusoidal endothelial cells: Physiology and role in liver diseases","volume":"66","author":"Poisson","year":"2017","journal-title":"J. Hepatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1002\/(SICI)1096-9896(199604)178:4<363::AID-PATH491>3.0.CO;2-8","article-title":"CD 105 and angiogenesis","volume":"178","author":"Kumar","year":"1996","journal-title":"J. Pathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/j.bbadis.2018.06.023","article-title":"Animal models of NAFLD from a hepatologist\u2019s point of view","volume":"1865","author":"Jahn","year":"2019","journal-title":"Biochim. Biophys. Acta Mol. Basis Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.endinu.2018.12.009","article-title":"Inflammatory stress and altered angiogenesis evoked by very high-fat diets in mouse liver","volume":"66","author":"Plaza","year":"2019","journal-title":"Endocrinol. Diabetes Nutr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1002\/hep.21338","article-title":"Leptin-mediated neovascularization is a prerequisite for progression of nonalcoholic steatohepatitis in rats","volume":"44","author":"Kitade","year":"2006","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1793","DOI":"10.1002\/hep.26219","article-title":"Role of vascular endothelial growth factor in the pathophysiology of nonalcoholic steatohepatitis in two rodent models","volume":"57","author":"Coulon","year":"2013","journal-title":"Hepatology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1002\/hep.30294","article-title":"Angiopoietin-2 Promotes Pathological Angiogenesis and Is a Therapeutic Target in Murine Nonalcoholic Fatty Liver Disease","volume":"69","author":"Lefere","year":"2019","journal-title":"Hepatology"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1002\/hep.27318","article-title":"Portal myofibroblasts promote vascular remodeling underlying cirrhosis formation through the release of microparticles","volume":"61","author":"Lemoinne","year":"2015","journal-title":"Hepatology"},{"key":"ref_15","first-page":"543","article-title":"Neovascularization and oxidative stress in the progression of non-alcoholic steatohepatitis","volume":"1","author":"Kitade","year":"2008","journal-title":"Mol. Med. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.cyto.2012.05.001","article-title":"Evaluation of inflammatory and angiogenic factors in patients with non-alcoholic fatty liver disease","volume":"59","author":"Coulon","year":"2012","journal-title":"Cytokine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1038\/ijo.2017.102","article-title":"Serum vascular cell adhesion molecule-1 predicts significant liver fibrosis in non-alcoholic fatty liver disease","volume":"41","author":"Lefere","year":"2017","journal-title":"Int. J. Obes."},{"key":"ref_18","first-page":"301","article-title":"Angiogenesis in the progression of non-alcoholic fatty liver disease","volume":"83","author":"Lefere","year":"2020","journal-title":"Acta Gastroenterol. Belg."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"684","DOI":"10.1002\/ar.20715","article-title":"Hepatic Microcirculation in Fatty Liver Disease","volume":"291","author":"Farrell","year":"2008","journal-title":"Anat. Rec. Adv. Integr. Anat. Evol. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s10620-017-4903-5","article-title":"Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease","volume":"63","author":"Baffy","year":"2018","journal-title":"Dig. Dis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1111\/cas.13902","article-title":"Ezetimibe suppresses development of liver tumors by inhibiting angiogenesis in mice fed a high-fat diet","volume":"110","author":"Miura","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1278","DOI":"10.1016\/j.jhep.2019.02.012","article-title":"Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease","volume":"70","author":"Hammoutene","year":"2019","journal-title":"J. Hepatol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/s41574-018-0096-z","article-title":"The role of hypoxia-inducible factors in metabolic diseases","volume":"15","author":"Gonzalez","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"79","DOI":"10.4103\/2277-9175.156526","article-title":"Leptin and its cardiovascular effects: Focus on angiogenesis","volume":"4","author":"Khazaei","year":"2015","journal-title":"Adv. Biomed. Res."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Dewidar, B., Meyer, C., Dooley, S., and Meindl-Beinker, N. (2019). TGF-beta in Hepatic Stellate Cell Activation and Liver Fibrogenesis-Updated 2019. Cells, 8.","DOI":"10.3390\/cells8111419"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2108","DOI":"10.2174\/138920111798808338","article-title":"TGF-beta receptor signaling pathways in angiogenesis; emerging targets for anti-angiogenesis therapy","volume":"12","author":"Goumans","year":"2011","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s12291-011-0121-7","article-title":"Role of Cytokines in the Pathogenesis of Non-Alcoholic Fatty Liver Disease","volume":"26","author":"Das","year":"2011","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1667","DOI":"10.1046\/j.1365-2036.2001.01083.x","article-title":"Plasma transforming growth factor-beta1 level and efficacy of alpha-tocopherol in patients with non-alcoholic steatohepatitis: A pilot study","volume":"15","author":"Hasegawa","year":"2001","journal-title":"Aliment Pharmacol. Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1002\/hep.27117","article-title":"Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis","volume":"60","author":"Granzow","year":"2014","journal-title":"Hepatology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.mce.2012.04.013","article-title":"The role of angiotensin II in nonalcoholic steatohepatitis","volume":"378","author":"Morris","year":"2013","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1016\/j.hepres.2006.07.003","article-title":"Angiotensin-II and vascular endothelial growth factor interaction plays an important role in rat liver fibrosis development","volume":"36","author":"Yoshiji","year":"2006","journal-title":"Hepatol. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jhepr.2019.02.004","article-title":"Macrophages in obesity and non-alcoholic fatty liver disease: Crosstalk with metabolism","volume":"1","author":"Lefere","year":"2019","journal-title":"JHEP Rep."},{"key":"ref_33","first-page":"512","article-title":"Resolving the fibrotic niche of human liver cirrhosis at single-cell level","volume":"575","author":"Ramachandran","year":"2019","journal-title":"Nat. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1002\/hep.29544","article-title":"Therapeutic inhibition of inflammatory monocyte recruitment reduces steatohepatitis and liver fibrosis","volume":"67","author":"Krenkel","year":"2018","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1136\/gutjnl-2013-306294","article-title":"CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis","volume":"63","author":"Ehling","year":"2014","journal-title":"Gut"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1124\/pr.112.005983","article-title":"Classification, functions, and clinical relevance of extracellular vesicles","volume":"64","author":"Harrison","year":"2012","journal-title":"Pharmacol. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1161\/CIRCRESAHA.117.309681","article-title":"Extracellular Vesicles in Angiogenesis","volume":"120","author":"Todorova","year":"2017","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nrgastro.2014.7","article-title":"The emerging roles of microvesicles in liver diseases","volume":"11","author":"Lemoinne","year":"2014","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1038\/nrgastro.2017.71","article-title":"Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets","volume":"14","author":"Szabo","year":"2017","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"ra88","DOI":"10.1126\/scisignal.2004512","article-title":"Lipid-Induced Toxicity Stimulates Hepatocytes to Release Angiogenic Microparticles That Require Vanin-1 for Uptake by Endothelial Cells","volume":"6","author":"Povero","year":"2013","journal-title":"Sci. Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"696","DOI":"10.1111\/apt.14937","article-title":"Systematic review with meta-analysis: Risk of hepatocellular carcinoma in non-alcoholic steatohepatitis without cirrhosis compared to other liver diseases","volume":"48","author":"Stine","year":"2018","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1136\/gutjnl-2014-308483","article-title":"Neoangiogenesis-related genes are hallmarks of fast-growing hepatocellular carcinomas and worst survival. Results from a prospective study","volume":"65","author":"Villa","year":"2016","journal-title":"Gut"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1053\/jhep.2002.32524","article-title":"Hypoxia-induced VEGF and collagen I expressions are associated with angiogenesis and fibrogenesis in experimental cirrhosis","volume":"35","author":"Corpechot","year":"2002","journal-title":"Hepatology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"588","DOI":"10.1002\/path.3005","article-title":"The biphasic nature of hypoxia-induced directional migration of activated human hepatic stellate cells","volume":"226","author":"Novo","year":"2011","journal-title":"J. Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1629","DOI":"10.1002\/hep.24238","article-title":"Inhibition of placental growth factor activity reduces the severity of fibrosis, inflammation, and portal hypertension in cirrhotic mice","volume":"53","author":"Ribera","year":"2011","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1007\/s00535-012-0651-7","article-title":"Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis","volume":"48","author":"Tamaki","year":"2013","journal-title":"J. Gastroenterol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1136\/gut.52.9.1347","article-title":"Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis","volume":"52","author":"Yoshiji","year":"2003","journal-title":"Gut"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1919","DOI":"10.1002\/hep.21921","article-title":"Antiangiogenic treatment with Sunitinib ameliorates inflammatory infiltrate, fibrosis, and portal pressure in cirrhotic rats","volume":"46","author":"Tugues","year":"2007","journal-title":"Hepatology"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1053\/j.gastro.2008.07.065","article-title":"Hepatic Stellate Cells Secrete Angiopoietin 1 That Induces Angiogenesis in Liver Fibrosis","volume":"135","author":"Taura","year":"2008","journal-title":"Gastroenterology"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1002\/hep.22758","article-title":"Beneficial effects of sorafenib on splanchnic, intrahepatic, and portocollateral circulations in portal hypertensive and cirrhotic rats","volume":"49","author":"Mejias","year":"2008","journal-title":"Hepatology"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1002\/hep.24427","article-title":"Complementary vascular and matrix regulatory pathways underlie the beneficial mechanism of action of sorafenib in liver fibrosis","volume":"54","author":"Thabut","year":"2011","journal-title":"Hepatology"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/labinvest.2010.148","article-title":"Hepatic and HSC-specific sorafenib effects in rats with established secondary biliary cirrhosis","volume":"91","author":"Hennenberg","year":"2010","journal-title":"Lab. Investig."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Huang, Y., Feng, H., Kan, T., Huang, B., Zhang, M., Li, Y., Shi, C., Wu, M., Luo, Y., and Yang, J. (2013). Bevacizumab Attenuates Hepatic Fibrosis in Rats by Inhibiting Activation of Hepatic Stellate Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0073492"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1053\/j.gastro.2014.01.061","article-title":"Vascular Endothelial Growth Factor Promotes Fibrosis Resolution and Repair in Mice","volume":"146","author":"Yang","year":"2014","journal-title":"Gastroenterology"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/7\/1338\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:40:14Z","timestamp":1760161214000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/10\/7\/1338"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,24]]},"references-count":54,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["jcm10071338"],"URL":"https:\/\/doi.org\/10.3390\/jcm10071338","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,24]]}}}