{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T12:04:43Z","timestamp":1782821083743,"version":"3.54.5"},"reference-count":41,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2017,10,21]],"date-time":"2017-10-21T00:00:00Z","timestamp":1508544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Venous leg ulcer (VLU) is a huge healthcare problem with poorly understood pathophysiology. Transforming growth factor-\u03b2 (TGF-\u03b2) and endoglin (Eng), are inflammatory and wound healing mediators. Eng, co-receptor for TGF-\u03b2 type-II receptors, may be cleaved forming soluble Eng (sEng), antagonizing TGF-\u03b2 signaling, a crucial process in vascular pathologies. We evaluated the accumulation in wound fluid (WF) of TGF-\u03b2 isoforms and sEng in healing stages, showing the effects of sulodexide treatments, a glycosaminoglycan with clinical efficacy in VLU healing. Patients with inflammatory (Infl) and granulating (Gran) VLU were recruited. WFs and THP-1 monocytes exposed to Infl and Gran WF (treated\/untreated with sulodexide) were analyzed for TGF-\u03b2 isoforms and sEng by multiplex immunoassay. In both Infl and Gran WF, TGF-\u03b21 and \u03b22 were similar; TGF-\u03b23 was significantly increased in Infl compared to Gran WFs (p = 0.033). sEng was significantly elevated in Gran compared to Infl WFs (p = 0.002). In THP-1 monocytes there was a significant increase in sEng after co-treatment of WF and sulodexide. The increase in TGF-\u03b23 found in Infl WF highlights its negative effect on wound healing, while the increased levels of sEng in Gran WF affects the leukocyte adhesion\/transmigration through the endothelium, reducing the inflammatory response and favoring the wound healing. Glycosaminoglycan sulodexide potentiates the effects of sEng release from monocyte, representing an important therapeutic option for wound healing.<\/jats:p>","DOI":"10.3390\/ijms18102206","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T04:32:19Z","timestamp":1508733139000},"page":"2206","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["Chronic Venous Insufficiency: Transforming Growth Factor-\u03b2 Isoforms and Soluble Endoglin Concentration in Different States of Wound Healing"],"prefix":"10.3390","volume":"18","author":[{"given":"Daniela","family":"Ligi","sequence":"first","affiliation":[{"name":"Department of Biomolecular Sciences, Section of Clinical Biochemistry and Molecular Genetics, University \u201cCarlo Bo\u201d, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidia","family":"Croce","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, Section of Clinical Biochemistry and Molecular Genetics, University \u201cCarlo Bo\u201d, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Mosti","sequence":"additional","affiliation":[{"name":"Department of Angiology, Barbantini Clinic, via del Calcio 2, 55100 Lucca, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Raffetto","sequence":"additional","affiliation":[{"name":"Vascular Surgery Division, VA Boston Healthcare System, West Roxbury, Boston, MA 02130, USA"},{"name":"Harvard Medical School, Brigham and Women\u2019s Hospital, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8112-6139","authenticated-orcid":false,"given":"Ferdinando","family":"Mannello","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Sciences, Section of Clinical Biochemistry and Molecular Genetics, University \u201cCarlo Bo\u201d, 61029 Urbino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,10,21]]},"reference":[{"key":"ref_1","first-page":"212","article-title":"Pathophysiology of chronic venous disease","volume":"33","author":"Raffetto","year":"2014","journal-title":"Int. Angiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1586\/14737159.2014.927312","article-title":"Omics profiles in chronic venous ulcer wound fluid: Innovative applications for translational medicine","volume":"14","author":"Mannello","year":"2014","journal-title":"Expert Rev. Mol. Diagn."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.jvsv.2015.10.002","article-title":"Pharmacologic treatment to improve venous leg ulcer healing","volume":"4","author":"Raffetto","year":"2016","journal-title":"J. Vasc. Surg. Venous. Lymphat. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1900","DOI":"10.1016\/j.bbadis.2016.07.011","article-title":"Chronic venous disease\u2014Part II: Proteolytic biomarkers in wound healing","volume":"1862","author":"Ligi","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1016\/j.bbadis.2016.07.018","article-title":"Chronic venous disease\u2014Part I: Inflammatory biomarkers in wound healing","volume":"1862","author":"Ligi","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1182\/blood-2012-06-435347","article-title":"Endothelial endoglin is involved in inflammation: Role in leukocyte adhesion and transmigration","volume":"121","author":"Rossi","year":"2013","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"585","DOI":"10.1111\/j.1524-475X.2008.00410.x","article-title":"Growth factors and cytokines in wound healing","volume":"16","author":"Barrientos","year":"2008","journal-title":"Wound Repair Regen."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1038\/ncb3528","article-title":"Endoglin controls blood vessel diameter through endothelial cell shape changes in response to haemodynamic cues","volume":"19","author":"Sudgen","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"195","DOI":"10.2147\/VHRM.S29144","article-title":"Endoglin: A critical mediator of cardiovascular health","volume":"9","author":"Kapur","year":"2013","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/cr.2008.326","article-title":"TGF-\u03b2 signaling in vascular biology and dysfunction","volume":"19","author":"Goumans","year":"2009","journal-title":"Cell Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"89","DOI":"10.3389\/fphys.2011.00089","article-title":"Transforming growth factor-\u03b2 and endoglin signaling orchestrate wound healing","volume":"2","author":"Valluru","year":"2011","journal-title":"Front. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1089\/wound.2012.0406","article-title":"Critical role of transforming growth factor \u03b2 in different phases of wound healing","volume":"2","author":"Pakyari","year":"2013","journal-title":"Adv. Wound Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/S1357-2725(96)00120-3","article-title":"Transforming growth factor \u03b2s and wound healing","volume":"29","author":"Ferguson","year":"1997","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1016\/S0741-5214(02)75295-6","article-title":"Altered proliferative responses of dermal fibroblasts to TGF-\u03b21 may contribute to chronic venous stasis ulcer","volume":"37","author":"Lal","year":"2003","journal-title":"J. Vasc. Surg."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1046\/j.0022-202x.2001.01501.x","article-title":"Effect of healing on the expression of transforming growth factor \u03b2(s) and their receptors in chronic venous leg ulcers","volume":"117","author":"Cowin","year":"2001","journal-title":"J. Investig. Dermatol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4894","DOI":"10.1073\/pnas.85.13.4894","article-title":"Transforming growth factor \u03b2 stimulates collagen-matrix contraction by fibroblasts: Implications for wound healing","volume":"85","author":"Montesano","year":"1988","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13221-014-0024-5","article-title":"Cellular and molecular basis of Venous insufficiency","volume":"6","author":"Pocock","year":"2014","journal-title":"Vasc. Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"92","DOI":"10.2119\/molmed.2009.00149","article-title":"Attenuation of the transforming growth factor \u03b2-signaling pathway in chronic venous ulcers","volume":"16","author":"Pastar","year":"2010","journal-title":"Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1038\/ncb3543","article-title":"Endoglin moves and shapes endothelial cells","volume":"19","author":"Bautch","year":"2017","journal-title":"Nat. Cell Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/PL00012413","article-title":"Inducible expression of human endoglin during inflammation and wound healing in vivo","volume":"51","author":"Torsney","year":"2002","journal-title":"Inflamm. Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"354","DOI":"10.2174\/1570161111311030010","article-title":"Glycosaminoglycan sulodexide inhibition of MMP-9 gelatinase secretion and activity: Possible pharmacological role against collagen degradation in vascular chronic diseases","volume":"11","author":"Mannello","year":"2013","journal-title":"Curr. Vasc. Pharmacol."},{"key":"ref_22","first-page":"229","article-title":"Pharmacological profile of sulodexide","volume":"33","author":"Hoppensteadt","year":"2014","journal-title":"Int. Angiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2165\/11599360-000000000-00000","article-title":"Sulodexide in the treatment of chronic venous disease","volume":"12","author":"Andreozzi","year":"2012","journal-title":"Am. J. Cardiovasc. Drugs"},{"key":"ref_24","first-page":"236","article-title":"Glycosaminoglycan sulodexide modulates inflammatory pathways in chronic venous disease","volume":"33","author":"Mannello","year":"2014","journal-title":"Int. Angiol."},{"key":"ref_25","first-page":"1","article-title":"Vascular pathologies and inflammation: The anti-inflammatory properties of sulodexide","volume":"19","author":"Mattana","year":"2012","journal-title":"J. Vasc. Endovasc. Surg."},{"key":"ref_26","first-page":"202","article-title":"Society for Vascular Surgery and American Venous Forum Guidelines on the management of venous leg ulcers: The point of view of the International Union of Phlebology","volume":"34","author":"Mosti","year":"2015","journal-title":"Int. Angiol."},{"key":"ref_27","first-page":"49","article-title":"Development and use of sulodexide in vascular diseases: Implications for treatment","volume":"8","author":"Coccheri","year":"2014","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"S66","DOI":"10.1016\/S0049-3848(09)70147-1","article-title":"Dermal pathology, cellular biology, and inflammation in chronic venous disease","volume":"123","author":"Raffetto","year":"2009","journal-title":"Thromb. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.1016\/j.jvs.2008.06.042","article-title":"The relationship between cytokine concentrations and wound healing in chronic venous ulceration","volume":"48","author":"Gohel","year":"2008","journal-title":"J. Vasc. Surg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1046\/j.1524-475X.1999.00442.x","article-title":"Analysis of the acute and chronic wound environments: The role of proteases and their inhibitors","volume":"7","author":"Trengove","year":"1999","journal-title":"Wound Repair Regen."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Gilbert, R., Vickaryous, M., and Viloria-Petit, A. (2016). Signalling by Transforming Growth Factor \u03b2 Isoforms in Wound Healing and Tissue Regeneration. J. Dev. Biol., 4.","DOI":"10.3390\/jdb4020021"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1046\/j.1524-475X.1996.40217.x","article-title":"Modulation of alpha-smooth muscle actin expression in fibroblasts by transforming growth factor-\u03b2 isoforms: An in vivo and in vitro study","volume":"4","author":"Serini","year":"1996","journal-title":"Wound Repair Regen."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S1359-6101(99)00037-4","article-title":"TGF-\u03b2 in blood: A complex problem","volume":"11","author":"Grainger","year":"2000","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_34","first-page":"1","article-title":"Cellular and molecular mechanisms of venous leg ulcers development\u2014The \u201cpuzzle\u201d theory","volume":"29","author":"Simka","year":"2010","journal-title":"Int. Angiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000272948","article-title":"Evaluation of transforming growth factor-\u03b2 signaling pathway in the wall of normal and varicose veins","volume":"77","author":"Kowalewski","year":"2010","journal-title":"Pathobiology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1074\/jbc.M105110200","article-title":"\u03b2glycan inhibits TGF-\u03b2 signaling by preventing type I-type II receptor complex formation: Glycosaminoglycan modifications alter betaglycan function","volume":"277","author":"Eickelberg","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/j.atherosclerosis.2015.10.003","article-title":"Soluble endoglin, hypercholesterolemia and endothelial dysfunction","volume":"243","author":"Rathouska","year":"2015","journal-title":"Atherosclerosis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1111\/wrr.12398","article-title":"Transforming growth factor \u03b2 isoforms in wound healing and fibrosis","volume":"24","author":"Lichtman","year":"2016","journal-title":"Wound Repair Regen."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1016\/S0741-5214(03)00424-5","article-title":"Definition of venous reflux in lower-extremity veins","volume":"38","author":"Labropoulos","year":"2003","journal-title":"J. Vasc. Surg."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1016\/j.jvs.2004.09.027","article-title":"Revision of the CEAP classification for chronic venous disorders: Consensus statement","volume":"40","author":"Eklof","year":"2004","journal-title":"J. Vasc. Surg."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1093\/bja\/aen103","article-title":"Assessment of pain","volume":"101","author":"Breivik","year":"2008","journal-title":"Br. J. Anaesth."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/10\/2206\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:48:03Z","timestamp":1760208483000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/18\/10\/2206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,21]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2017,10]]}},"alternative-id":["ijms18102206"],"URL":"https:\/\/doi.org\/10.3390\/ijms18102206","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,21]]}}}