Upon inflammation, monocyte-derived macrophages (MΦ) infiltrate blood vessels to regulate several processes involved in vascular pathophysiology. However, little is known about the mediators involved. Macrophage polarization is crucial for a fast and efficient initial response (GM-MΦ) and a good resolution (M-MΦ) of the inflammatory process. The functional activity of polarized MΦ is exerted mainly through their secretome, which can target other cell types, including endothelial cells. Endoglin (CD105) is a cell surface receptor expressed by endothelial cells and MΦ that is markedly upregulated in inflammation and critically involved in angiogenesis. In addition, a soluble form of endoglin with anti-angiogenic activity has been described in inflammation-associated pathologies. The aim of this work was to identify components of the MΦ secretome involved in the shedding of soluble endoglin. We find that the GM-MΦ secretome contains metalloprotease 12 (MMP-12), a GM-MΦ specific marker that may account for the anti-angiogenic activity of the GM-MΦ secretome. Cell surface endoglin is present in both GM-MΦ and M-MΦ, but soluble endoglin is only detected in GM-MΦ culture supernatants. Moreover, MMP-12 is responsible for the shedding of soluble endoglin in vitro and in vivo by targeting membrane-bound endoglin in both MΦ and endothelial cells. These data demonstrate a direct correlation between GM-MΦ polarization, MMP-12, and soluble endoglin expression and function. By targeting endothelial cells, MMP-12 may represent a novel mediator involved in vascular homeostasis.

Centro de Investigación Biomédica en Red de Enfermedades Raras 28040 Madrid Spain

Centro de Investigaciones Biológicas Consejo Superior de Investigaciones Científicas 28040 Madrid Spain

Department of Biological and Medical Sciences Faculty of Pharmacy in Hradec Kralove Charles University 500 05 Hradec Kralove Czech Republic

Zobrazit více v PubMed

Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008;454:428–435. doi: 10.1038/nature07201. PubMed DOI

Mosser D.M., Edwards J.P. Exploring the full spectrum of macrophage activation. Nat. Rev. Immunol. 2008;8:958–969. doi: 10.1038/nri2448. PubMed DOI PMC

Shirai T., Hilhorst M., Harrison D.G., Goronzy J.J., Weyand C.M. Macrophages in vascular inflammation-From atherosclerosis to vasculitis. Autoimmunity. 2015;48:139–151. doi: 10.3109/08916934.2015.1027815. PubMed DOI PMC

Honold L., Nahrendorf M. Resident and monocyte-derived macrophages in cardiovascular disease. Circ. Res. 2018;122:113–127. doi: 10.1161/CIRCRESAHA.117.311071. PubMed DOI PMC

Moore K.J., Koplev S., Fisher E.A., Tabas I., Björkegren J.L.M., Doran A.C., Kovacic J.C. Macrophage trafficking, inflammatory resolution, and genomics in atherosclerosis: JACC macrophage in CVD series (Part 2) J. Am. Coll. Cardiol. 2018;72:2181–2197. doi: 10.1016/j.jacc.2018.08.2147. PubMed DOI PMC

Guo L., Akahori H., Harari E., Smith S.L., Polavarapu R., Karmali V., Otsuka F., Gannon R.L., Braumann R.E., Dickinson M.H., et al. CD163+ macrophages promote angiogenesis and vascular permeability accompanied by inflammation in atherosclerosis. J. Clin. Investig. 2018;128:1106–1124. doi: 10.1172/JCI93025. PubMed DOI PMC

Decano J.L., Aikawa M. Dynamic macrophages: Understanding mechanisms of activation as guide to therapy for atherosclerotic vascular disease. Front. Cardiovasc. Med. 2018;5:97. doi: 10.3389/fcvm.2018.00097. PubMed DOI PMC

Harrison D.G., Marvar P.J., Titze J.M. Vascular inflammatory cells in hypertension. Front. Physiol. 2012;3:128. doi: 10.3389/fphys.2012.00128. PubMed DOI PMC

Shahid F., Lip G.Y.H., Shantsila E. Role of monocytes in heart failure and atrial fibrillation. J. Am. Heart Assoc. 2018;7:e007849. doi: 10.1161/JAHA.117.007849. PubMed DOI PMC

Jaipersad A.S., Lip G.Y., Silverman S., Shantsila E. The role of monocytes in angiogenesis and atherosclerosis. J. Am. Coll. Cardiol. 2014;63:1–11. doi: 10.1016/j.jacc.2013.09.019. PubMed DOI

Gerhardt T., Ley K. Monocyte trafficking across the vessel wall. Cardiovasc. Res. 2015;107:321–330. doi: 10.1093/cvr/cvv147. PubMed DOI PMC

Cui K., Ardell C.L., Podolnikova N.P., Yakubenko V.P. Distinct migratory properties of M1, M2, and resident macrophages are regulated by αDβ2 and αMβ2 integrin-mediated adhesion. Front. Immunol. 2018;9:2650. doi: 10.3389/fimmu.2018.02650. PubMed DOI PMC

Rossi E., Sanz-Rodriguez F., Eleno N., Düwell A., Blanco F.J., Langa C., Botella L.M., Cabañas C., Lopez-Novoa J.M., Bernabeu C. Endothelial endoglin is involved in inflammation: Role in leukocyte adhesion and transmigration. Blood. 2013;121:403–415. doi: 10.1182/blood-2012-06-435347. PubMed DOI

Vestweber D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 2015;15:692–704. doi: 10.1038/nri3908. PubMed DOI

Ruffell B., Coussens L.M. Macrophages and therapeutic resistance in cancer. Cancer Cell. 2015;27:462–472. doi: 10.1016/j.ccell.2015.02.015. PubMed DOI PMC

Escribese M.M., Sierra-Filardi E., Nieto C., Samaniego R., Sánchez-Torres C., Matsuyama T., Calderon-Gómez E., Vega M.A., Salas A., Sánchez-Mateos P., et al. The prolyl hydroxylase PHD3 identifies proinflammatory macrophages and its expression is regulated by activin A. J. Immunol. 2012;189:1946–1954. doi: 10.4049/jimmunol.1201064. PubMed DOI

Sierra-Filardi E., Puig-Kröger A., Blanco F.J., Nieto C., Bragado R., Palomero M.I., Bernabéu C., Vega M.A., Corbí A.L. Activin A skews macrophage polarization by promoting a proinflammatory phenotype and inhibiting the acquisition of anti-inflammatory macrophage markers. Blood. 2011;117:5092–5101. doi: 10.1182/blood-2010-09-306993. PubMed DOI

Van Hinsbergh V.W., Koolwijk P. Endothelial sprouting and angiogenesis: Matrix metalloproteinases in the lead. Cardiovasc. Res. 2008;78:203–212. doi: 10.1093/cvr/cvm102. PubMed DOI

Nissinen L., Kähäri V.M. Matrix metalloproteinases in inflammation. Biochim. Biophys. Acta. 2014;1840:2571–2580. doi: 10.1016/j.bbagen.2014.03.007. PubMed DOI

Shapiro S.D., Kobayashi D.K., Ley T.J. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J. Biol. Chem. 1993;268:23824–23829. PubMed

De las Casas-Engel M., Domínguez-Soto A., Sierra-Filardi E., Bragado R., Nieto C., Puig-Kroger A., Samaniego R., Loza M., Corcuera M.T., Gómez-Aguado F., et al. Serotonin skews human macrophage polarization through HTR2B and HTR7. J. Immunol. 2013;190:2301–2310. doi: 10.4049/jimmunol.1201133. PubMed DOI

Palacios B.S., Estrada-Capetillo L., Izquierdo E., Criado G., Nieto C., Municio C., González-Alvaro I., Sánchez-Mateos P., Pablos J.L., Corbí A.L., et al. Macrophages from the synovium of active rheumatoid arthritis exhibit an activin A-dependent pro-inflammatory profile. J. Pathol. 2015;235:515–526. doi: 10.1002/path.4466. PubMed DOI

Wu L., Tanimoto A., Murata Y., Fan J., Sasaguri Y., Watanabe T. Induction of human matrix metalloproteinase-12 gene transcriptional activity by GM-CSF requires the AP-1 binding site in human U937 monocytic cells. Biochem. Biophys. Res. Commun. 2001;285:300–307. doi: 10.1006/bbrc.2001.5161. PubMed DOI

Holmström S.B., Clark R., Zwicker S., Bureik D., Kvedaraite E., Bernasconi E., Hoang A.T.N., Johannsen G., Marsland B.J., Boström E.A., et al. Gingival tissue inflammation promotes increased matrix metalloproteinase-12 production by CD200Rlow monocyte-derived cells in periodontitis. J. Immunol. 2017;199:4023–4035. doi: 10.4049/jimmunol.1700672. PubMed DOI

Mahdessian H., Matic L.P., Lengquist M., Gertow K., Sennblad B., Baldassarre D., Veglia F., Humphries S.E., Rauramaa R., de Faire U., et al. Integrative studies implicate matrix metalloproteinase-12 as a culprit gene for large-artery atherosclerotic stroke. J. Intern. Med. 2017;282:429–444. doi: 10.1111/joim.12655. PubMed DOI

Liu S.L., Bajpai A., Hawthorne E.A., Bae Y., Castagnino P., Monslow J., Puré E., Spiller K.L., Assoian R.K. Cardiovascular protection in females linked to estrogen-dependent inhibition of arterial stiffening and macrophage MMP12. JCI Insight. 2019;4:122742. doi: 10.1172/jci.insight.122742. PubMed DOI PMC

Amin M., Pushpakumar S., Muradashvili N., Kundu S., Tyagi S.C., Sen U. Regulation and involvement of matrix metalloproteinases in vascular diseases. Front. Biosci. 2016;21:89–118. PubMed PMC

Scholtes V.P., Johnson J.L., Jenkins N., Sala-Newby G.B., de Vries J.P., de Borst G.J., de Kleijn D.P., Moll F.L., Pasterkamp G., Newby A.C. Carotid atherosclerotic plaque matrix metalloproteinase-12-positive macrophage subpopulation predicts adverse outcome after endarterectomy. J. Am. Heart Assoc. 2012;1:e001040. doi: 10.1161/JAHA.112.001040. PubMed DOI PMC

Johnson J.L., Devel L., Czarny B., George S.J., Jackson C.L., Rogakos V., Beau F., Yiotakis A., Newby A.C., Dive V. A selective matrix metalloproteinase-12 inhibitor retards atherosclerotic plaque development in apolipoprotein E-knockout mice. Arterioscler. Thromb. Vasc. Biol. 2011;31:528–535. doi: 10.1161/ATVBAHA.110.219147. PubMed DOI PMC

D’Alessio S., Fibbi G., Cinelli M., Guiducci S., Del Rosso A., Margheri F., Serratì S., Pucci M., Kahaleh B., Fan P., et al. Matrix metalloproteinase 12-dependent cleavage of urokinase receptor in systemic sclerosis microvascular endothelial cells results in impaired angiogenesis. Arthritis Rheum. 2004;50:3275–3285. doi: 10.1002/art.20562. PubMed DOI

Margheri F., Serratì S., Lapucci A., Chillà A., Bazzichi L., Bombardieri S., Kahaleh B., Calorini L., Bianchini F., Fibbi G., et al. Modulation of the angiogenic phenotype of normal and systemic sclerosis endothelial cells by gain-loss of function of pentraxin 3 and matrix metalloproteinase 12. Arthritis Rheum. 2010;62:2488–2498. doi: 10.1002/art.27522. PubMed DOI

Chan M.F., Li J., Bertrand A., Casbon A.J., Lin J.H., Maltseva I., Werb Z. Protective effects of matrix metalloproteinase-12 following corneal injury. J. Cell Sci. 2013;126:3948–3960. doi: 10.1242/jcs.128033. PubMed DOI PMC

Laurenzana A., Biagioni A., D’Alessio S., Bianchini F., Chillà A., Margheri F., Luciani C., Mazzanti B., Pimpinelli N., Torre E., et al. Melanoma cell therapy: Endothelial progenitor cells as shuttle of the MMP12 uPAR-degrading enzyme. Oncotarget. 2014;5:3711–3727. doi: 10.18632/oncotarget.1987. PubMed DOI PMC

Wolf M., Maltseva I., Clay S.M., Pan P., Gajjala A., Chan M.F. Effects of MMP12 on cell motility and inflammation during corneal epithelial repair. Exp. Eye Res. 2017;160:11–20. doi: 10.1016/j.exer.2017.04.007. PubMed DOI PMC

Cheifetz S., Bellón T., Calés C., Vera S., Bernabeu C., Massagué J., Letarte M. Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells. J. Biol. Chem. 1992;267:19027–19030. PubMed

Lastres P., Bellon T., Cabañas 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;22:393–397. doi: 10.1002/eji.1830220216. PubMed DOI

O’Connell P.J., McKenzie A., Fisicaro N., Rockman S.P., Pearse M.J., d’Apice A.J. Endoglin: A 180-kD endothelial cell and macrophage restricted differentiation molecule. Clin. Exp. Immunol. 1992;90:154–159. doi: 10.1111/j.1365-2249.1992.tb05848.x. PubMed DOI PMC

Ruiz-Llorente L., Gallardo-Vara E., Rossi E., Smadja D.M., Botella L.M., Bernabeu C. Endoglin and alk1 as therapeutic targets for hereditary hemorrhagic telangiectasia. Expert Opin. Ther. Targets. 2017;21:933–947. doi: 10.1080/14728222.2017.1365839. PubMed DOI

López-Novoa J.M., Bernabeu C. The physiological role of endoglin in the cardiovascular system. Am. J. Physiol. Heart Circ. Physiol. 2010;299:H959–H974. doi: 10.1152/ajpheart.01251.2009. PubMed DOI

Venkatesha S., Toporsian M., Lam C., Hanai J., Mammoto T., Kim Y.M., Bdolah Y., Lim K.H., Yuan H.T., Libermann T.A., et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat. Med. 2006;12:642–649. doi: 10.1038/nm1429. PubMed DOI

Bernabeu C., Lopez-Novoa J.M., Quintanilla M. The emerging role of TGF-beta superfamily coreceptors in cancer. Biochim. Biophys. Acta. 2009;1792:954–973. doi: 10.1016/j.bbadis.2009.07.003. PubMed DOI

Torsney E., Charlton R., Parums D., Collis M., Arthur H.M. Inducible expression of human endoglin during inflammation and wound healing in vivo. Inflamm. Res. 2002;51:464–470. doi: 10.1007/PL00012413. PubMed DOI

Ermini L., Ausman J., Melland-Smith M., Yeganeh B., Rolfo A., Litvack M.L., Todros T., Letarte M., Post M., Caniggia I. A single sphingomyelin species promotes exosomal release of endoglin into the maternal circulation in preeclampsia. Sci. Rep. 2017;7:12172. doi: 10.1038/s41598-017-12491-4. PubMed DOI PMC

Honsawek S., Tanavalee A., Yuktanandana P. Elevated circulating and synovial fluid endoglin are associated with primary knee osteoarthritis severity. Arch. Med. Res. 2009;40:590–594. doi: 10.1016/j.arcmed.2009.07.010. PubMed DOI

Blázquez-Medela A.M., García-Ortiz L., Gómez-Marcos M.A., Recio-Rodríguez J.I., Sánchez-Rodríguez A., López-Novoa J.M., Martínez-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

Gregory A.L., Xu G., Sotov V., Letarte M. Review: The enigmatic role of endoglin in the placenta. Placenta. 2014;35:S93–S99. doi: 10.1016/j.placenta.2013.10.020. PubMed DOI

Gallardo-Vara E., Tual-Chalot S., Botella L.M., Arthur H.M., Bernabeu C. Soluble endoglin regulates expression of angiogenesis-related proteins and induction of arteriovenous malformations in a mouse model of hereditary hemorrhagic telangiectasia. Dis. Models Mech. 2018;11:dmm034397. doi: 10.1242/dmm.034397. PubMed DOI PMC

Li C., Guo B., Ding S., Rius C., Langa C., Kumar P., Bernabeu C., Kumar S. TNF alpha down-regulates CD105 expression in vascular endothelial cells: A comparative study with TGF beta 1. Anticancer Res. 2003;23:1189–1196. PubMed

Sunderland N.S., Thomson S.E., Heffernan S.J., Lim S., Thompson J., Ogle R., McKenzie P., Kirwan P.J., Makris A., Hennessy A. Tumor necrosis factor α induces a model of preeclampsia in pregnant baboons (Papio hamadryas) Cytokine. 2011;56:192–199. doi: 10.1016/j.cyto.2011.06.003. PubMed DOI

Kumar S., Pan C.C., Bloodworth J.C., Nixon A.B., Theuer C., Hoyt D.G., Lee N.Y. Antibody-directed coupling of endoglin and MMP-14 is a key mechanism for endoglin shedding and deregulation of TGF-β signaling. Oncogene. 2014;33:3970–3979. doi: 10.1038/onc.2013.386. PubMed DOI PMC

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

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

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

Jezkova K., Rathouska J., Nemeckova I., Fikrova P., Dolezelova E., Varejckova M., Vitverova B., Tysonova K., Serwadczak A., Buczek E., et al. 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;53:149–162. doi: 10.1159/000448996. PubMed DOI

Vitverova B., Blazickova K., Najmanova I., Vicen M., Hyšpler R., Dolezelova E., Nemeckova I., Tebbens J.D., Bernabeu C., Pericacho M., et al. 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

Li W., Li J., Wu Y., Wu J., Hotchandani R., Cunningham K., McFadyen I., Bard J., Morgan P., Schlerman F., et al. A selective matrix metalloprotease 12 inhibitor for potential treatment of chronic obstructive pulmonary disease (COPD): Discovery of (S)-2-(8-(methoxycarbonylamino)dibenzo[b,d]furan-3-sulfonamido)-3-methylbutanoic acid (MMP408) J. Med. Chem. 2009;52:1799–1802. doi: 10.1021/jm900093d. PubMed DOI

Valbuena-Diez A.C., Blanco F.J., Oujo B., Langa C., Gonzalez-Nuñez M., Llano E., Pendas A.M., Díaz M., Castrillo A., Lopez-Novoa J.M., et al. Oxysterol-induced soluble endoglin release and its involvement in hypertension. Circulation. 2012;126:2612–2624. doi: 10.1161/CIRCULATIONAHA.112.101261. PubMed DOI

Raffort J., Lareyre F., Clément M., Hassen-Khodja R., Chinetti G., Mallat Z. Monocytes and macrophages in abdominal aortic aneurysm. Nat. Rev. Cardiol. 2017;14:457–471. doi: 10.1038/nrcardio.2017.52. PubMed DOI

Decano J.L., Mattson P.C., Aikawa M. Macrophages in vascular inflammation: Origins and functions. Curr. Atheroscler. Rep. 2016;18:34. doi: 10.1007/s11883-016-0585-2. PubMed DOI

Liu M., Sun H., Wang X., Koike T., Mishima H., Ikeda K., Watanabe T., Ochiai N., Fan J. Association of increased expression of macrophage elastase (matrix metalloproteinase 12) with rheumatoid arthritis. Arthritis Rheum. 2004;50:3112–3117. doi: 10.1002/art.20567. PubMed DOI

Pohl D., Andrýs C., Borská L., Fiala Z., Hamaková K., Ettler K., Krejsek J. Serum level of a soluble form of endoglin (CD105) is decreased after Goeckerman’s therapy of psoriasis. Acta Med. (Hradec Kral.) 2011;54:59–62. doi: 10.14712/18059694.2016.19. PubMed DOI

Rulo H.F., Westphal J.R., van de Kerkhof P.C., de Waal R.M., van Vlijmen I.M., Ruiter D.J. Expression of endoglin in psoriatic involved and uninvolved skin. J. Dermatol. Sci. 1995;10:103–109. doi: 10.1016/0923-1811(95)00397-B. PubMed DOI

Van de Kerkhof P.C., Rulo H.F., van Pelt J.P., van Vlijmen-Willems I.M., De Jong E.M. Expression of endoglin in the transition between psoriatic uninvolved and involved skin. Acta Derm. Venereol. 1998;78:19–21. doi: 10.1080/00015559850135760. PubMed DOI

Ojeda-Fernández L., Recio-Poveda L., Aristorena M., Lastres P., Blanco F.J., Sanz-Rodríguez F., Gallardo-Vara E., de las Casas-Engel M., Corbí Á., Arthur H.M., et al. Mice lacking endoglin in macrophages show an impaired immune response. PLoS Genet. 2016;12:e1005935. doi: 10.1371/journal.pgen.1005935. PubMed DOI PMC

Dupuis-Girod S., Giraud S., Decullier E., Lesca G., Cottin V., Faure F., Merrot O., Saurin J.C., Cordier J.F., Plauchu H. Hemorrhagic hereditary telangiectasia (Rendu-Osler disease) and infectious diseases: An underestimated association. Clin. Infect. Dis. 2007;44:841–845. doi: 10.1086/511645. PubMed DOI

Shovlin C.L. Hereditary haemorrhagic telangiectasia: Pathophysiology, diagnosis and treatment. Blood Rev. 2010;24:203–219. doi: 10.1016/j.blre.2010.07.001. PubMed DOI

Peter M.R., Jerkic M., Sotov V., Douda D.N., Ardelean D.S., Ghamami N., Lakschevitz F., Khan M.A., Robertson S.J., Glogauer M., et al. Impaired resolution of inflammation in the Endoglin heterozygous mouse model of chronic colitis. Mediat. Inflamm. 2014;2014:767185. doi: 10.1155/2014/767185. PubMed DOI PMC

Rossi E., Lopez-Novoa J.M., Bernabeu C. Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1) Front. Genet. 2015;5:457. doi: 10.3389/fgene.2014.00457. PubMed DOI PMC

Van Laake L.W., van den Driesche S., Post S., Feijen A., Jansen M.A., Driessens M.H., Mager J.J., Snijder R.J., Westermann C.J., Doevendans P.A., et al. Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation. 2006;114:2288–2297. doi: 10.1161/CIRCULATIONAHA.106.639161. PubMed DOI

Schneider C.A., Rasband W.S., Eliceiri K.W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods. 2012;9:671–675. doi: 10.1038/nmeth.2089. PubMed DOI PMC

Ruiz-Llorente L., Chiapparino E., Plumitallo S., Danesino C., Bayrak-Toydemir P., Pagella F., Manfredi G., Bernabeu C., Jovine L., Olivieri C. Characterization of a mutation in the zona pellucida module of endoglin that causes hereditary hemorrhagic telangiectasia. Gene. 2019;696:33–39. doi: 10.1016/j.gene.2019.02.016. PubMed DOI

Guerrero-Esteo M., Sanchez-Elsner T., Letamendia A., Bernabeu C. Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II. J. Biol. Chem. 2002;277:29197–29209. doi: 10.1074/jbc.M111991200. PubMed DOI

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

Membrane and soluble endoglin role in cardiovascular and metabolic disorders related to metabolic syndrome

Soluble Endoglin as a Potential Biomarker of Nonalcoholic Steatohepatitis (NASH) Development, Participating in Aggravation of NASH-Related Changes in Mouse Liver