Membrane endoglin (Eng, CD105) is a transmembrane glycoprotein essential for the proper function of vascular endothelium. It might be cleaved by matrix metalloproteinases to form soluble endoglin (sEng), which is released into the circulation. Metabolic syndrome comprises conditions/symptoms that usually coincide (endothelial dysfunction, arterial hypertension, hyperglycemia, obesity-related insulin resistance, and hypercholesterolemia), and are considered risk factors for cardiometabolic disorders such as atherosclerosis, type II diabetes mellitus, and liver disorders. The purpose of this review is to highlight current knowledge about the role of Eng and sEng in the disorders mentioned above, in vivo and in vitro extent, where we can find a wide range of contradictory results. We propose that reduced Eng expression is a hallmark of endothelial dysfunction development in chronic pathologies related to metabolic syndrome. Eng expression is also essential for leukocyte transmigration and acute inflammation, suggesting that Eng is crucial for the regulation of endothelial function during the acute phase of vascular defense reaction to harmful conditions. sEng was shown to be a circulating biomarker of preeclampsia, and we propose that it might be a biomarker of metabolic syndrome-related symptoms and pathologies, including hypercholesterolemia, hyperglycemia, arterial hypertension, and diabetes mellitus as well, despite the fact that some contradictory findings have been reported. Besides, sEng can participate in the development of endothelial dysfunction and promote the development of arterial hypertension, suggesting that high levels of sEng promote metabolic syndrome symptoms and complications. Therefore, we suggest that the treatment of metabolic syndrome should take into account the importance of Eng in the endothelial function and levels of sEng as a biomarker and risk factor of related pathologies.

Faculty of Medicine in Hradec Kralove Department of Pharmacology Charles University Simkova 870 Hradec Kralove 500 03 Czech Republic

Faculty of Pharmacy in Hradec Kralove Department of Biological and Medical Sciences Charles University Heyrovskeho 1203 Hradec Kralove 500 03 Czech Republic

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Oujo B, Perez-Barriocanal F, Bernabeu C, Lopez-Novoa JM. Membrane and soluble forms of endoglin in preeclampsia. Curr Mol Med. 2013;13(8):1345–1357. doi: 10.2174/15665240113139990058. PubMed DOI

Bot PT, Hoefer IE, Sluijter JP, van Vliet P, Smits AM, Lebrin F, Moll F, de Vries JP, Doevendans P, Piek JJ, Pasterkamp G, Goumans MJ. Increased expression of the transforming growth factor-beta signaling pathway, endoglin, and early growth response-1 in stable plaques. Stroke. 2009;40(2):439–447. doi: 10.1161/STROKEAHA.108.522284. PubMed DOI

St-Jacques S, Forte M, Lye SJ, Letarte M. Localization of endoglin, a transforming growth factor-beta binding protein, and of CD44 and integrins in placenta during the first trimester of pregnancy. Biol Reprod. 1994;51(3):405–413. doi: 10.1095/biolreprod51.3.405. PubMed DOI

Meurer S, Wimmer AE, Leur EV, Weiskirchen R. Endoglin trafficking/exosomal targeting in liver cells depends on n-glycosylation. Cells. 2019 doi: 10.3390/cells8090997. PubMed DOI PMC

Lastres P, Bellon T, Cabanas C, Sanchez-Madrid F, Acevedo A, Gougos A, Letarte M, Bernabeu C. Regulated expression on human macrophages of endoglin, an Arg-Gly-Asp-containing surface antigen. Eur J Immunol. 1992;22(2):393–397. doi: 10.1002/eji.1830220216. PubMed DOI

McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J, et al. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8(4):345–351. doi: 10.1038/ng1294-345. PubMed DOI

Kapur NK, Morine KJ, Letarte M. Endoglin: a critical mediator of cardiovascular health. Vasc Health Risk Manag. 2013;9:195–206. doi: 10.2147/VHRM.S29144. PubMed DOI PMC

Qu R, Silver MM, Letarte M. Distribution of endoglin in early human development reveals high levels on endocardial cushion tissue mesenchyme during valve formation. Cell Tissue Res. 1998;292(2):333–343. doi: 10.1007/s004410051064. PubMed DOI

Alsamman M, Sterzer V, Meurer SK, Sahin H, Schaeper U, Kuscuoglu D, Strnad P, Weiskirchen R, Trautwein C, Scholten D. Endoglin in human liver disease and murine models of liver fibrosis-A protective factor against liver fibrosis. Liver Int. 2018;38(5):858–867. doi: 10.1111/liv.13595. PubMed DOI PMC

Vicen M, Vitverova B, Havelek R, Blazickova K, Machacek M, Rathouska J, Najmanova I, Dolezelova E, Prasnicka A, Sternak M, Bernabeu C, Nachtigal P. Regulation and role of endoglin in cholesterol-induced endothelial and vascular dysfunction in vivo and in vitro. FASEB J. 2019;33(5):6099–6114. doi: 10.1096/fj.201802245R. PubMed DOI

Rossi E, Sanz-Rodriguez F, Eleno N, Duwell A, Blanco FJ, Langa C, Botella LM, Cabanas C, Lopez-Novoa JM, Bernabeu C. Endothelial endoglin is involved in inflammation: role in leukocyte adhesion and transmigration. Blood. 2013;121(2):403–415. doi: 10.1182/blood-2012-06-435347. PubMed DOI

Aristorena M, Gallardo-Vara E, Vicen M, de Las C-E, Ojeda-Fernandez L, Nieto C, Blanco FJ, Valbuena-Diez AC, Botella LM, Nachtigal P, Corbi AL, Colmenares M, Bernabeu C. MMP-12, Secreted by pro-inflammatory macrophages, targets endoglin in human macrophages and endothelial cells. Int J Mol Sci. 2019 doi: 10.3390/ijms20123107. PubMed DOI PMC

Hawinkels LJ, Kuiper P, Wiercinska E, Verspaget HW, Liu Z, Pardali E, Sier CF, ten Dijke P. Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis. Cancer Res. 2010;70(10):4141–4150. doi: 10.1158/0008-5472.CAN-09-4466. PubMed DOI

Valbuena-Diez AC, Blanco FJ, Oujo B, Langa C, Gonzalez-Nunez M, Llano E, Pendas AM, Diaz M, Castrillo A, Lopez-Novoa JM, Bernabeu C. Oxysterol-induced soluble endoglin release and its involvement in hypertension. Circulation. 2012;126(22):2612–2624. doi: 10.1161/CIRCULATIONAHA.112.101261. PubMed DOI

Blaha M, Cermanova M, Blaha V, Jarolim P, Andrys C, Blazek M, Maly J, Smolej L, Zajic J, Masin V, Zimova R, Rehacek V. Elevated serum soluble endoglin (sCD105) decreased during extracorporeal elimination therapy for familial hypercholesterolemia. Atherosclerosis. 2008;197(1):264–270. doi: 10.1016/j.atherosclerosis.2007.04.022. PubMed DOI

Blann AD, Wang JM, Wilson PB, Kumar S. Serum levels of the TGF-beta receptor are increased in atherosclerosis. Atherosclerosis. 1996;120(1–2):221–226. doi: 10.1016/0021-9150(95)05713-7. PubMed DOI

Malhotra R, Paskin-Flerlage S, Zamanian RT, Zimmerman P, Schmidt JW, Deng DY, Southwood M, Spencer R, Lai CS, Parker W, Channick RN, Morrell NW, Elliott CG, Yu PB. Circulating angiogenic modulatory factors predict survival and functional class in pulmonary arterial hypertension. Pulm Circ. 2013;3(2):369–380. doi: 10.4103/2045-8932.110445. PubMed DOI PMC

Leanos-Miranda A, Navarro-Romero CS, Sillas-Pardo LJ, Ramirez-Valenzuela KL, Isordia-Salas I, Jimenez-Trejo LM. Soluble endoglin as a marker for preeclampsia, its severity, and the occurrence of adverse outcomes. Hypertension. 2019;74(4):991–997. doi: 10.1161/HYPERTENSIONAHA.119.13348. PubMed DOI

Doghish AS, Bassyouni AA, Mahfouz MH, Abd El-Aziz HG, Zakaria RY. Plasma endoglin in Type2 diabetic patients with nephropathy. Diabetes Metab Syndr. 2019;13(1):764–768. doi: 10.1016/j.dsx.2018.11.058. PubMed DOI

Rathouska J, Nemeckova I, Zemankova L, Strasky Z, Jezkova K, Varejckova M, Nachtigal P. Cell adhesion molecules and eNOS expression in aorta of normocholesterolemic mice with different predispositions to atherosclerosis. Heart Vessels. 2015;30(2):241–248. doi: 10.1007/s00380-014-0493-8. PubMed DOI

Nachtigal P, Zemankova Vecerova L, Rathouska J, Strasky Z. The role of endoglin in atherosclerosis. Atherosclerosis. 2012;224(1):4–11. doi: 10.1016/j.atherosclerosis.2012.03.001. PubMed DOI

Schoonderwoerd MJA, Goumans MTH, Hawinkels L. Endoglin: beyond the endothelium. Biomolecules. 2020 doi: 10.3390/biom10020289. PubMed DOI PMC

Xu G, Barrios-Rodiles M, Jerkic M, Turinsky AL, Nadon R, Vera S, Voulgaraki D, Wrana JL, Toporsian M, Letarte M. Novel protein interactions with endoglin and activin receptor-like kinase 1: potential role in vascular networks. Mol Cell Proteom: MCP. 2014;13(2):489–502. doi: 10.1074/mcp.M113.033464. PubMed DOI PMC

Gougos A, Letarte M. Primary structure of endoglin, an RGD-containing glycoprotein of human endothelial cells. J Biol Chem. 1990;265(15):8361–8364. doi: 10.1016/S0021-9258(19)38892-1. PubMed DOI

Llorca O, Trujillo A, Blanco FJ, Bernabeu C. Structural model of human endoglin, a transmembrane receptor responsible for hereditary hemorrhagic telangiectasia. J Mol Biol. 2007;365(3):694–705. doi: 10.1016/j.jmb.2006.10.015. PubMed DOI

Velasco S, Alvarez-Munoz P, Pericacho M, Dijke PT, Bernabeu C, Lopez-Novoa JM, Rodriguez-Barbero A. L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts. J Cell Sci. 2008;121(Pt 6):913–919. doi: 10.1242/jcs.023283. PubMed DOI

Blanco FJ, Grande MT, Langa C, Oujo B, Velasco S, Rodriguez-Barbero A, Perez-Gomez E, Quintanilla M, Lopez-Novoa JM, Bernabeu C. S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology. Circ Res. 2008;103(12):1383–1392. doi: 10.1161/CIRCRESAHA.108.176552. PubMed DOI

Conley BA, Smith JD, Guerrero-Esteo M, Bernabeu C, Vary CP. Endoglin, a TGF-beta receptor-associated protein, is expressed by smooth muscle cells in human atherosclerotic plaques. Atherosclerosis. 2000;153(2):323–335. doi: 10.1016/S0021-9150(00)00422-6. PubMed DOI

Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004;109(23 Suppl 1):III27–32. PubMed

Jerkic M, Rivas-Elena JV, Prieto M, Carron R, Sanz-Rodriguez F, Perez-Barriocanal F, Rodriguez-Barbero A, Bernabeu C, Lopez-Novoa JM. Endoglin regulates nitric oxide-dependent vasodilatation. FASEB J. 2004;18(3):609–611. doi: 10.1096/fj.03-0197fje03-0197fje[pii]. PubMed DOI

Toporsian M, Gros R, Kabir MG, Vera S, Govindaraju K, Eidelman DH, Husain M, Letarte M. A role for endoglin in coupling eNOS activity and regulating vascular tone revealed in hereditary hemorrhagic telangiectasia. Circ Res. 2005;96(6):684–692. doi: 10.1161/01.RES.0000159936.38601.22. PubMed DOI

Santibanez JF, Letamendia A, Perez-Barriocanal F, Silvestri C, Saura M, Vary CP, Lopez-Novoa JM, Attisano L, Bernabeu C. Endoglin increases eNOS expression by modulating Smad2 protein levels and Smad2-dependent TGF-beta signaling. J Cell Physiol. 2007;210(2):456–468. doi: 10.1002/jcp.20878. PubMed DOI

Zemankova L, Varejckova M, Dolezalova E, Fikrova P, Jezkova K, Rathouska J, Cerveny L, Botella LM, Bernabeu C, Nemeckova I, Nachtigal P. Atorvastatin-induced endothelial nitric oxide synthase expression in endothelial cells is mediated by endoglin. J Physiol Pharmacol. 2015;66(3):403–413. PubMed

Jerkic M, Letarte M. Increased endothelial cell permeability in endoglin-deficient cells. FASEB J. 2015;29(9):3678–3688. doi: 10.1096/fj.14-269258. PubMed DOI

Anderberg C, Cunha SI, Zhai Z, Cortez E, Pardali E, Johnson JR, Franco M, Paez-Ribes M, Cordiner R, Fuxe J, Johansson BR, Goumans MJ, Casanovas O, ten Dijke P, Arthur HM, Pietras K. Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med. 2013;210(3):563–579. doi: 10.1084/jem.20120662. PubMed DOI PMC

Rossini R, Capodanno D, Ferrero P, Gargiulo G, Capranzano P. Management issues of chronic therapy with non-vitamin K oral anticoagulants or antiplatelet agents: different or alike? Int J Cardiol. 2016;221:695–696. doi: 10.1016/j.ijcard.2016.07.008. PubMed DOI

Ojeda-Fernandez L, Recio-Poveda L, Aristorena M, Lastres P, Blanco FJ, Sanz-Rodriguez F, Gallardo-Vara E, de las Casas-Engel M, Corbi A, Arthur HM, Bernabeu C, Botella LM. Mice lacking endoglin in macrophages show an impaired immune response. PLoS Genet. 2016;12(3):e1005935. doi: 10.1371/journal.pgen.1005935. PubMed DOI PMC

Botella LM, Sanchez-Elsner T, Sanz-Rodriguez F, Kojima S, Shimada J, Guerrero-Esteo M, Cooreman MP, Ratziu V, Langa C, Vary CP, Ramirez JR, Friedman S, Bernabeu C. Transcriptional activation of endoglin and transforming growth factor-beta signaling components by cooperative interaction between Sp1 and KLF6: their potential role in the response to vascular injury. Blood. 2002;100(12):4001–4010. doi: 10.1182/blood.V100.12.4001100/12/4001[pii]. PubMed DOI

Gallardo-Vara E, Blanco FJ, Roque M, Friedman SL, Suzuki T, Botella LM, Bernabeu C. Transcription factor KLF6 upregulates expression of metalloprotease MMP14 and subsequent release of soluble endoglin during vascular injury. Angiogenesis. 2016;19(2):155–171. doi: 10.1007/s10456-016-9495-8. PubMed DOI PMC

Sanchez-Elsner T, Botella LM, Velasco B, Langa C, Bernabeu C. Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways. J Biol Chem. 2002;277(46):43799–43808. doi: 10.1074/jbc.M207160200M207160200[pii]. PubMed DOI

van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J. 2008;412(3):477–484. doi: 10.1042/BJ20080476. PubMed DOI PMC

Henry-Berger J, Mouzat K, Baron S, Bernabeu C, Marceau G, Saru JP, Sapin V, Lobaccaro JM, Caira F. Endoglin (CD105) expression is regulated by the liver X receptor alpha (NR1H3) in human trophoblast cell line JAR. Biol Reprod. 2008;78(6):968–975. doi: 10.1095/biolreprod.107.066498. PubMed DOI

Csanyi G, Gajda M, Franczyk-Zarow M, Kostogrys R, Gwozdz P, Mateuszuk L, Sternak M, Wojcik L, Zalewska T, Walski M, Chlopicki S. Functional alterations in endothelial NO, PGI(2) and EDHF pathways in aorta in ApoE/LDLR-/- mice. Prostaglandins Other Lipid Mediat. 2012;98(3–4):107–115. doi: 10.1016/j.prostaglandins.2012.02.002. PubMed DOI

Vecerova L, Strasky Z, Rathouska J, Slanarova M, Brcakova E, Micuda S, Nachtigal P. Activation of TGF-beta receptors and Smad proteins by atorvastatin is related to reduced atherogenesis in ApoE/LDLR double knockout mice. J Atheroscler Thromb. 2012;19(2):115–126. doi: 10.5551/jat.8185. PubMed DOI

Strasky Z, Vecerova L, Rathouska J, Slanarova M, Brcakova E, Kudlackova Z, Andrys C, Micuda S, Nachtigal P. Cholesterol effects on endoglin and its downstream pathways in ApoE/LDLR double knockout mice. Circ J. 2011;75(7):1747–1755. doi: 10.1253/circj.CJ-10-1285. PubMed DOI

Rathouska J, Vecerova L, Strasky Z, Slanarova M, Brcakova E, Mullerova Z, Andrys C, Micuda S, Nachtigal P. Endoglin as a possible marker of atorvastatin treatment benefit in atherosclerosis. Pharmacol Res. 2011;64(1):53–59. doi: 10.1016/j.phrs.2011.03.008. PubMed DOI

Alvarez-Munoz P, Mauer M, Kim Y, Rich SS, Miller ME, Russell GB, Lopez-Novoa JM, Caramori ML. Cellular basis of diabetic nephropathy: V. Endoglin expression levels and diabetic nephropathy risk in patients with type 1 diabetes. J Diabetes Complicat. 2010;24(4):242–249. doi: 10.1016/j.jdiacomp.2009.03.004. PubMed DOI PMC

La Sala L, Pujadas G, De Nigris V, Canivell S, Novials A, Genovese S, Ceriello A. Oscillating glucose and constant high glucose induce endoglin expression in endothelial cells: the role of oxidative stress. Acta Diabetol. 2015;52(3):505–512. doi: 10.1007/s00592-014-0670-3. PubMed DOI

Wang S, Hirschberg R. Diabetes-relevant regulation of cultured blood outgrowth endothelial cells. Microvasc Res. 2009;78(2):174–179. doi: 10.1016/j.mvr.2009.06.002. PubMed DOI PMC

Rinella ME. Nonalcoholic fatty liver disease: a systematic review. JAMA. 2015;313(22):2263–2273. doi: 10.1001/jama.2015.5370. PubMed DOI

Finnson KW, Philip A. Endoglin in liver fibrosis. J Cell Commun Signal. 2012;6(1):1–4. doi: 10.1007/s12079-011-0154-y. PubMed DOI PMC

Garcia-Pozo L, Miquilena-Colina ME, Lozano-Rodriguez T, Garcia-Monzon C. Endoglin: structure, biological functions, and role in fibrogenesis. Rev Esp Enferm Dig. 2008;100(6):355–360. doi: 10.4321/s1130-01082008000600008. PubMed DOI

Meurer SK, Tihaa L, Borkham-Kamphorst E, Weiskirchen R. Expression and functional analysis of endoglin in isolated liver cells and its involvement in fibrogenic Smad signalling. Cell Signal. 2011;23(4):683–699. doi: 10.1016/j.cellsig.2010.12.002. PubMed DOI

Meurer SK, Alsamman M, Scholten D, Weiskirchen R. Endoglin in liver fibrogenesis: bridging basic science and clinical practice. World J Biol Chem. 2014;5(2):180–203. doi: 10.4331/wjbc.v5.i2.180. PubMed DOI PMC

Chan DC, Barrett HP, Watts GF. Dyslipidemia in visceral obesity: mechanisms, implications, and therapy. Am J Cardiovasc Drugs. 2004;4(4):227–246. doi: 10.2165/00129784-200404040-00004. PubMed DOI

Kurki E, Shi J, Martonen E, Finckenberg P, Mervaala E. Distinct effects of calorie restriction on adipose tissue cytokine and angiogenesis profiles in obese and lean mice. Nutr Metab (Lond) 2012;9(1):64. doi: 10.1186/1743-7075-9-64. PubMed DOI PMC

Jilkova ZM, Hensler M, Medrikova D, Janovska P, Horakova O, Rossmeisl M, Flachs P, Sell H, Eckel J, Kopecky J. Adipose tissue-related proteins locally associated with resolution of inflammation in obese mice. Int J Obes (Lond) 2014;38(2):216–223. doi: 10.1038/ijo.2013.108. PubMed DOI

Vanlaere I, Libert C. Matrix metalloproteinases as drug targets in infections caused by gram-negative bacteria and in septic shock. Clin Microbiol Rev. 2009;22(2):224–239. doi: 10.1128/CMR.00047-08. PubMed DOI PMC

Vandenbroucke RE, Libert C. Is there new hope for therapeutic matrix metalloproteinase inhibition? Nat Rev Drug Discov. 2014;13(12):904–927. doi: 10.1038/nrd4390. PubMed DOI

Klein T, Bischoff R. Physiology and pathophysiology of matrix metalloproteases. Amino Acids. 2011;41(2):271–290. doi: 10.1007/s00726-010-0689-x. PubMed DOI PMC

Feinberg MW, Jain MK, Werner F, Sibinga NE, Wiesel P, Wang H, Topper JN, Perrella MA, Lee ME. Transforming growth factor-beta 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. J Biol Chem. 2000;275(33):25766–25773. doi: 10.1074/jbc.M002664200. PubMed DOI

Rajavashisth TB, Xu XP, Jovinge S, Meisel S, Xu XO, Chai NN, Fishbein MC, Kaul S, Cercek B, Sharifi B, Shah PK. Membrane type 1 matrix metalloproteinase expression in human atherosclerotic plaques: evidence for activation by proinflammatory mediators. Circulation. 1999;99(24):3103–3109. doi: 10.1161/01.cir.99.24.3103. PubMed DOI

Rathouska J, Jezkova K, Nemeckova I, Nachtigal P. Soluble endoglin, hypercholesterolemia and endothelial dysfunction. Atherosclerosis. 2015;243(2):383–388. doi: 10.1016/j.atherosclerosis.2015.10.003. PubMed DOI

Li Q, Lin F, Ke D, Cheng Q, Gui Y, Zhou Y, Wu Y, Wang Y, Zhu P. Combination of endoglin and ASCVD risk assessment improves carotid subclinical atherosclerosis recognition. J Atheroscler Thromb. 2020;27(4):331–341. doi: 10.5551/jat.50898. PubMed DOI PMC

Saita E, Miura K, Suzuki-Sugihara N, Miyata K, Ikemura N, Ohmori R, Ikegami Y, Kishimoto Y, Kondo K, Momiyama Y. Plasma soluble endoglin levels are inversely associated with the severity of coronary atherosclerosis-brief report. Arterioscler Thromb Vasc Biol. 2017;37(1):49–52. doi: 10.1161/ATVBAHA.116.308494. PubMed DOI

Charytan DM, Cinelli A, Zeisberg EM. Association of circulating angiogenesis inhibitors and asymmetric dimethyl arginine with coronary plaque burden. Fibrogenesis Tissue Repair. 2015;8:13. doi: 10.1186/s13069-015-0029-6. PubMed DOI PMC

Blazquez-Medela AM, Garcia-Ortiz L, Gomez-Marcos MA, Recio-Rodriguez JI, Sanchez-Rodriguez A, Lopez-Novoa JM, Martinez-Salgado C. Increased plasma soluble endoglin levels as an indicator of cardiovascular alterations in hypertensive and diabetic patients. BMC Med. 2010;8:86. doi: 10.1186/1741-7015-8-86. PubMed DOI PMC

Bilir B, Ekiz Bilir B, Yilmaz I, Soysal Atile N, Yildirim T, Kara SP, Gumustas SA, Orhan AE, Aydin M. Association of apelin, endoglin and endocan with diabetic peripheral neuropathy in type 2 diabetic patients. Eur Rev Med Pharmacol Sci. 2016;20(5):892–898. PubMed

Ekiz-Bilir B, Bilir B, Aydin M, Soysal-Atile N. Evaluation of endocan and endoglin levels in chronic kidney disease due to diabetes mellitus. Arch Med Sci. 2019;15(1):86–91. doi: 10.5114/aoms.2018.79488. PubMed DOI PMC

Ceriello A, La Sala L, De Nigris V, Pujadas G, Testa R, Uccellatore A, Genovese S. GLP-1 reduces metalloproteinase-14 and soluble endoglin induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Endocrine. 2015;50(2):508–511. doi: 10.1007/s12020-015-0565-2. PubMed DOI

Cawyer C, Afroze SH, Drever N, Allen S, Jones R, Zawieja DC, Kuehl T, Uddin MN. Attenuation of hyperglycemia-induced apoptotic signaling and anti-angiogenic milieu in cultured cytotrophoblast cells. Hypertens Pregnancy. 2016;35(2):159–169. doi: 10.3109/10641955.2015.1122035. PubMed DOI

Cawyer CR, Horvat D, Leonard D, Allen SR, Jones RO, Zawieja DC, Kuehl TJ, Uddin MN. Hyperglycemia impairs cytotrophoblast function via stress signaling. Am J Obstet Gynecol. 2014;211(5):e541–548. doi: 10.1016/j.ajog.2014.04.033. PubMed DOI

Lappas M. Markers of endothelial cell dysfunction are increased in human omental adipose tissue from women with pre-existing maternal obesity and gestational diabetes. Metab Clin Exp. 2014;63(6):860–873. doi: 10.1016/j.metabol.2014.03.007. PubMed DOI

Vieira MC, Poston L, Fyfe E, Gillett A, Kenny LC, Roberts CT, Baker PN, Myers JE, Walker JJ, McCowan LM, North RA, Pasupathy D, Consortium S Clinical and biochemical factors associated with preeclampsia in women with obesity. Obesity (Silver Spring) 2017;25(2):460–467. doi: 10.1002/oby.21715. PubMed DOI

Coral-Alvarado PX, Garces MF, Caminos JE, Iglesias-Gamarra A, Restrepo JF, Quintana G. Serum endoglin levels in patients suffering from systemic sclerosis and elevated systolic pulmonary arterial pressure. Int J Rheumatol. 2010 doi: 10.1155/2010/969383. PubMed DOI PMC

Bakouboula B, Morel O, Faure A, Zobairi F, Jesel L, Trinh A, Zupan M, Canuet M, Grunebaum L, Brunette A, Desprez D, Chabot F, Weitzenblum E, Freyssinet JM, Chaouat A, Toti F. Procoagulant membrane microparticles correlate with the severity of pulmonary arterial hypertension. Am J Respir Crit Care Med. 2008;177(5):536–543. doi: 10.1164/rccm.200706-840OC. PubMed DOI

Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12(6):642–649. doi: 10.1038/nm1429. PubMed DOI

Walshe TE, Dole VS, Maharaj AS, Patten IS, Wagner DD, D'Amore PA. Inhibition of VEGF or TGF-{beta} signaling activates endothelium and increases leukocyte rolling. Arterioscler Thromb Vasc Biol. 2009;29(8):1185–1192. doi: 10.1161/ATVBAHA.109.186742. PubMed DOI PMC

Varejckova M, Gallardo-Vara E, Vicen M, Vitverova B, Fikrova P, Dolezelova E, Rathouska J, Prasnicka A, Blazickova K, Micuda S, Bernabeu C, Nemeckova I, Nachtigal P. Soluble endoglin modulates the pro-inflammatory mediators NF-kappaB and IL-6 in cultured human endothelial cells. Life Sci. 2017;175:52–60. doi: 10.1016/j.lfs.2017.03.014. PubMed DOI

Kapur NK, Wilson S, Yunis AA, Qiao X, Mackey E, Paruchuri V, Baker C, Aronovitz MJ, Karumanchi SA, Letarte M, Kass DA, Mendelsohn ME, Karas RH. Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure. Circulation. 2012;125(22):2728–2738. doi: 10.1161/CIRCULATIONAHA.111.080002. PubMed DOI PMC

Munoz-Felix JM, Gonzalez-Nunez M, Lopez-Novoa JM. ALK1-Smad1/5 signaling pathway in fibrosis development: friend or foe? Cytokine Growth Factor Rev. 2013;24(6):523–537. doi: 10.1016/j.cytogfr.2013.08.002. PubMed DOI

Pannu J, Nakerakanti S, Smith E, ten Dijke P, Trojanowska M. Transforming growth factor-beta receptor type I-dependent fibrogenic gene program is mediated via activation of Smad1 and ERK1/2 pathways. J Biol Chem. 2007;282(14):10405–10413. doi: 10.1074/jbc.M611742200. PubMed DOI

Wiercinska E, Wickert L, Denecke B, Said HM, Hamzavi J, Gressner AM, Thorikay M, ten Dijke P, Mertens PR, Breitkopf K, Dooley S. Id1 is a critical mediator in TGF-beta-induced transdifferentiation of rat hepatic stellate cells. Hepatology. 2006;43(5):1032–1041. doi: 10.1002/hep.21135. PubMed DOI

Dituri F, Cossu C, Mancarella S, Giannelli G. The interactivity between TGFbeta and BMP signaling in organogenesis, fibrosis, and cancer. Cells. 2019 doi: 10.3390/cells8101130. PubMed DOI PMC

Breitkopf-Heinlein K, Meyer C, Konig C, Gaitantzi H, Addante A, Thomas M, Wiercinska E, Cai C, Li Q, Wan F, Hellerbrand C, Valous NA, Hahnel M, Ehlting C, Bode JG, Muller-Bohl S, Klingmuller U, Altenoder J, Ilkavets I, Goumans MJ, Hawinkels LJ, Lee SJ, Wieland M, Mogler C, Ebert MP, Herrera B, Augustin H, Sanchez A, Dooley S, Ten Dijke P. BMP-9 interferes with liver regeneration and promotes liver fibrosis. Gut. 2017;66(5):939–954. doi: 10.1136/gutjnl-2016-313314. PubMed DOI

Lawera A, Tong Z, Thorikay M, Redgrave RE, Cai J, van Dinther M, Morrell NW, Afink GB, Charnock-Jones DS, Arthur HM, Ten Dijke P, Li W. Role of soluble endoglin in BMP9 signaling. Proc Natl Acad Sci U S A. 2019;116(36):17800–17808. doi: 10.1073/pnas.1816661116. PubMed DOI PMC

Ruiz-Remolina L, Ollauri-Ibanez C, Perez-Roque L, Nunez-Gomez E, Perez-Barriocanal F, Lopez-Novoa JM, Pericacho M, Rodriguez-Barbero A. Circulating soluble endoglin modifies the inflammatory response in mice. PLoS ONE. 2017;12(11):e0188204. doi: 10.1371/journal.pone.0188204. PubMed DOI PMC

Nemeckova I, Serwadczak A, Oujo B, Jezkova K, Rathouska J, Fikrova P, Varejckova M, Bernabeu C, Lopez-Novoa JM, Chlopicki S, Nachtigal P. High soluble endoglin levels do not induce endothelial dysfunction in mouse aorta. PLoS ONE. 2015;10(3):e0119665. doi: 10.1371/journal.pone.0119665. PubMed DOI PMC

Jezkova K, Rathouska J, Nemeckova I, Fikrova P, Dolezelova E, Varejckova M, Vitverova B, Tysonova K, Serwadczak A, Buczek E, Bernabeu C, Lopez-Novoa JM, Chlopicki S, Nachtigal P. High levels of soluble endoglin induce a proinflammatory and oxidative-stress phenotype associated with preserved NO-dependent vasodilatation in aortas from mice fed a high-fat diet. J Vasc Res. 2016;53(3–4):149–162. doi: 10.1159/000448996. PubMed DOI

Gallardo-Vara E, Gamella-Pozuelo L, Perez-Roque L, Bartha JL, Garcia-Palmero I, Casal JI, Lopez-Novoa JM, Pericacho M, Bernabeu C. Potential role of circulating endoglin in hypertension via the upregulated expression of BMP4. Cells. 2020 doi: 10.3390/cells9040988. PubMed DOI PMC

Vitverova B, Blazickova K, Najmanova I, Vicen M, Hyspler R, Dolezelova E, Nemeckova I, Tebbens JD, Bernabeu C, Pericacho M, Nachtigal P. Soluble endoglin and hypercholesterolemia aggravate endothelial and vessel wall dysfunction in mouse aorta. Atherosclerosis. 2018;271:15–25. doi: 10.1016/j.atherosclerosis.2018.02.008. PubMed DOI

Dolezelova E, Sa ICI, Prasnicka A, Hroch M, Hyspler R, Ticha A, Lastuvkova H, Cermanova J, Pericacho M, Visek J, Lasticova M, Micuda S, Nachtigal P. High soluble endoglin levels regulate cholesterol homeostasis and bile acids turnover in the liver of transgenic mice. Life Sci. 2019;232:116643. doi: 10.1016/j.lfs.2019.116643. PubMed DOI

Nachtigal P, Pospisilova N, Vecerova L, Micuda S, Brcakova E, Pospechova K, Semecky V. Atorvastatin increases endoglin, SMAD2, phosphorylated SMAD2/3 and eNOS expression in ApoE/LDLR double knockout mice. J Atheroscler Thromb. 2009;16(3):265–274. doi: 10.5551/jat.E745. PubMed DOI

Giordano A, Romano S, Monaco M, Sorrentino A, Corcione N, Di Pace AL, Ferraro P, Nappo G, Polimeno M, Romano MF. Differential effect of atorvastatin and tacrolimus on proliferation of vascular smooth muscle and endothelial cells. Am J Physiol Heart Circ Physiol. 2012;302(1):H135–142. doi: 10.1152/ajpheart.00490.2011. PubMed DOI

Zemankova L, Varejckova M, Dolezelova E, Fikrova P, Jezkova K, Rathouska J, Cerveny L, Botella LM, Bernabeu C, Nemeckova I, Nachtigal P. Atorvastatin-induced endothelial nitric oxide synthase expression in endothelial cells is mediated by endoglin. J Physiol Pharmacol. 2015;66(3):403–413. PubMed

Shyu KG, Wang BW, Chen WJ, Kuan P, Hung CR. Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor-beta1 in cultured cardiac fibroblasts. Eur J Heart Fail. 2010;12(3):219–226. doi: 10.1093/eurjhf/hfq011. PubMed DOI

Brownfoot FC, Tong S, Hannan NJ, Hastie R, Cannon P, Kaitu'u-Lino TJ. Effects of simvastatin, rosuvastatin and pravastatin on soluble fms-like tyrosine kinase 1 (sFlt-1) and soluble endoglin (sENG) secretion from human umbilical vein endothelial cells, primary trophoblast cells and placenta. BMC Pregnancy Childbirth. 2016;16:117. doi: 10.1186/s12884-016-0902-3. PubMed DOI PMC

Romero R, Erez O, Huttemann M, Maymon E, Panaitescu B, Conde-Agudelo A, Pacora P, Yoon BH, Grossman LI. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity. Am J Obstet Gynecol. 2017;217(3):282–302. doi: 10.1016/j.ajog.2017.06.003. PubMed DOI PMC

Buda V, Andor M, Baibata DE, Cozlac R, Radu G, Coricovac D, Danciu C, Ledeti I, Cheveresan A, Nica C, Tuduce P, Tomescu MC. Decreased sEng plasma levels in hypertensive patients with endothelial dysfunction under chronic treatment with Perindopril. Drug Des Devel Ther. 2019;13:1915–1925. doi: 10.2147/DDDT.S186378. PubMed DOI PMC

Hannan NJ, Brownfoot FC, Cannon P, Deo M, Beard S, Nguyen TV, Palmer KR, Tong S, Kaitu'u-Lino TJ. Resveratrol inhibits release of soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin and improves vascular dysfunction—implications as a preeclampsia treatment. Scientific Reports. 2017;7(1):1819. doi: 10.1038/s41598-017-01993-w. PubMed DOI PMC

Liu Y, Tian H, Blobe GC, Theuer CP, Hurwitz HI, Nixon AB. Effects of the combination of TRC105 and bevacizumab on endothelial cell biology. Invest New Drugs. 2014;32(5):851–859. doi: 10.1007/s10637-014-0129-y. PubMed DOI PMC

Kumar S, Pan CC, Bloodworth JC, Nixon AB, Theuer C, Hoyt DG, Lee NY. Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-beta signaling. Oncogene. 2014;33(30):3970–3979. doi: 10.1038/onc.2013.386. PubMed DOI PMC

Labetalol and soluble endoglin aggravate bile acid retention in mice with ethinylestradiol-induced cholestasis

Monoclonal anti-endoglin antibody TRC105 (carotuximab) prevents hypercholesterolemia and hyperglycemia-induced endothelial dysfunction in human aortic endothelial cells

Prognostic value of soluble endoglin in patients with septic shock and severe COVID-19

High Soluble Endoglin Levels Affect Aortic Vascular Function during Mice Aging