Thromb Haemost 2022; 122(09): 1513-1523
DOI: 10.1055/a-1772-0574
Cellular Signalling and Proteolysis

Changes in Endocan and Dermatan Sulfate Are Associated with Biomechanical Properties of Abdominal Aortic Wall during Aneurysm Expansion and Rupture

Susanne Metschl
1   Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
,
Lukas Bruder
3   Mechanics and High Performance Computing Group, Technical University of Munich, Munich, Germany
,
1   Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
,
Katharina Jakob
1   Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
,
Benedikt Reutersberg
1   Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
4   Department of Vascular Surgery, University Hospital Zurich, Zurich, Switzerland
,
Christian Reeps
5   Department of Visceral, Thoracic, and Vascular Surgery, Medizinische Fakultät an der TU-Dresden, Dresden, Germany
,
Lars Maegdefessel
1   Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
,
Michael Gee
3   Mechanics and High Performance Computing Group, Technical University of Munich, Munich, Germany
,
Hans-Henning Eckstein
1   Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
,
1   Department of Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
2   German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany
4   Department of Vascular Surgery, University Hospital Zurich, Zurich, Switzerland
› Institutsangaben
Funding This study was funded by the German Research Foundation (Deutsche Forschungs-gemeinschaft, DFG) (project number GZ: RE3146/1-1 and GE2254/1-1).

Abstract

Background and Aims The study aimed to assess the potential of proteoglycans (PGs) and collagens as serological biomarkers in the abdominal aortic aneurysm (AAA). Furthermore, we investigated the underlying mechano-biological interactions and signaling pathways.

Methods Tissue and serum samples from patients with ruptured AAA (rAAA; n = 29), elective AAA (eAAA; n = 78), and healthy individuals (n = 8) were evaluated by histology, immunohistochemistry, and enzyme-linked immunosorbent assay, and mechanical properties were assessed by tensile tests. Regulatory pathways were determined by membrane-based sandwich immunoassay.

Results In AAA samples, collagen type I and III (Col1 and Col3), chondroitin sulfate, and dermatan sulfate (DS) were significantly increased compared with controls (3.0-, 3.2-, 1.3-, and 53-fold; p < 0.01). Col1 and endocan were also elevated in the serum of AAA patients (3.6- and 6.0-fold; p < 0.01), while DS was significantly decreased (2.5-fold; p < 0.01). Histological scoring showed increased total PGs and focal accumulation in rAAA compared with eAAA. Tissue β-stiffness was higher in rAAA compared with eAAA (2.0-fold, p = 0.02). Serum Col1 correlated with maximum tensile force and failure tension (r = 0.448 and 0.333; p < 0.01, and r = 0.02), tissue endocan correlated with α-stiffness (r = 0.340; p < 0.01). Signaling pathways in AAA were associated with extracellular matrix synthesis and vascular smooth muscle cell proliferation. In particular, Src family kinases and platelet-derived growth factor- and epidermal growth factor-related proteins seem to be involved.

Conclusion Our findings reveal a structural association between collagen and PGs and their response to changes in mechanical loads in AAA. Particularly Col1 and endocan reflect the mechano-biological conditions of the aortic wall also in the patient's serum and might serve for AAA risk stratification.

Supplementary Material



Publikationsverlauf

Eingereicht: 19. September 2021

Angenommen: 12. Februar 2022

Accepted Manuscript online:
15. Februar 2022

Artikel online veröffentlicht:
18. Mai 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Nordon IM, Hinchliffe RJ, Loftus IM, Thompson MM. Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol 2011; 8 (02) 92-102
  • 2 Chaikof EL, Dalman RL, Eskandari MK. et al. The Society for Vascular Surgery practice guidelines on the care of patients with an abdominal aortic aneurysm. J Vasc Surg 2018; 67 (01) 2.e2-77.e2
  • 3 Torres-Fonseca M, Galan M, Martinez-Lopez D. et al; En representación del Grupo de trabajo de Biología Vascular de la Sociedad Española de Arteriosclerosis. Pathophisiology of abdominal aortic aneurysm: biomarkers and novel therapeutic targets. Clin Investig Arterioscler 2019; 31 (04) 166-177
  • 4 Wanhainen A, Mani K, Golledge J. Surrogate markers of abdominal aortic aneurysm progression. Arterioscler Thromb Vasc Biol 2016; 36 (02) 236-244
  • 5 Davis FM, Daugherty A, Lu HS. Updates of recent aortic aneurysm research. Arterioscler Thromb Vasc Biol 2019; 39 (03) e83-e90
  • 6 Daugherty A, Cassis LA. Mechanisms of abdominal aortic aneurysm formation. Curr Atheroscler Rep 2002; 4 (03) 222-227
  • 7 Vorp DA. Biomechanics of abdominal aortic aneurysm. J Biomech 2007; 40 (09) 1887-1902
  • 8 Wagenseil JE, Mecham RP. Vascular extracellular matrix and arterial mechanics. Physiol Rev 2009; 89 (03) 957-989
  • 9 Humphrey JD, Schwartz MA, Tellides G, Milewicz DM. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ Res 2015; 116 (08) 1448-1461
  • 10 Lindahl U, Couchman J, Kimata K, Esko JD. Proteoglycans and sulfated glycosaminoglycans. In: Varki A, Cummings RD, Esko JD, et al., eds. Essentials of Glycobiology Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2015: 207-221
  • 11 Figueroa JE, Oubre J, Vijayagopal P. Modulation of vascular smooth muscle cells proteoglycan synthesis by the extracellular matrix. J Cell Physiol 2004; 198 (02) 302-309
  • 12 Scott JE. Proteoglycan-fibrillar collagen interactions. Biochem J 1988; 252 (02) 313-323
  • 13 Béchard D, Gentina T, Delehedde M. et al. Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem 2001; 276 (51) 48341-48349
  • 14 Tanios F, Gee MW, Pelisek J. et al. Interaction of biomechanics with extracellular matrix components in abdominal aortic aneurysm wall. Eur J Vasc Endovasc Surg 2015; 50 (02) 167-174
  • 15 Leung DY, Glagov S, Mathews MB. Cyclic stretching stimulates synthesis of matrix components by arterial smooth muscle cells in vitro. Science 1976; 191 (4226): 475-477
  • 16 Reeps C, Maier A, Pelisek J. et al. Measuring and modeling patient-specific distributions of material properties in abdominal aortic aneurysm wall. Biomech Model Mechanobiol 2013; 12 (04) 717-733
  • 17 Schindelin J, Arganda-Carreras I, Frise E. et al. Fiji: an open-source platform for biological-image analysis. Nat Methods 2012; 9 (07) 676-682
  • 18 Yasmin, Maskari RA, McEniery CM. et al. The matrix proteins aggrecan and fibulin-1 play a key role in determining aortic stiffness. Sci Rep 2018; 8 (01) 8550
  • 19 Kelleher CM, McLean SE, Mecham RP. Vascular extracellular matrix and aortic development. Curr Top Dev Biol 2004; 62: 153-188
  • 20 Theocharis AD, Tsolakis I, Tzanakakis GN, Karamanos NK. Chondroitin sulfate as a key molecule in the development of atherosclerosis and cancer progression. Adv Pharmacol 2006; 53: 281-295
  • 21 Satta J, Juvonen T, Haukipuro K, Juvonen M, Kairaluoma MI. Increased turnover of collagen in abdominal aortic aneurysms, demonstrated by measuring the concentration of the aminoterminal propeptide of type III procollagen in peripheral and aortal blood samples. J Vasc Surg 1995; 22 (02) 155-160
  • 22 Treska V, Topolcan O. Plasma and tissue levels of collagen types I and III markers in patients with abdominal aortic aneurysms. Int Angiol 2000; 19 (01) 64-68
  • 23 Tatara Y, Kakizaki I, Suto S, Ishioka H, Negishi M, Endo M. Chondroitin sulfate cluster of epiphycan from salmon nasal cartilage defines binding specificity to collagens. Glycobiology 2015; 25 (05) 557-569
  • 24 Kvist AJ, Johnson AE, Mörgelin M. et al. Chondroitin sulfate perlecan enhances collagen fibril formation. Implications for perlecan chondrodysplasias. J Biol Chem 2006; 281 (44) 33127-33139
  • 25 Joladarashi D, Salimath PV, Chilkunda ND. Diabetes results in structural alteration of chondroitin sulfate/dermatan sulfate in the rat kidney: effects on the binding to extracellular matrix components. Glycobiology 2011; 21 (07) 960-972
  • 26 Trowbridge JM, Gallo RL. Dermatan sulfate: new functions from an old glycosaminoglycan. Glycobiology 2002; 12 (09) 117R-125R
  • 27 Iozzo RV, Schaefer L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol 2015; 42: 11-55
  • 28 Annovi G, Boraldi F, Moscarelli P. et al. Heparan sulfate affects elastin deposition in fibroblasts cultured from donors of different ages. Rejuvenation Res 2012; 15 (01) 22-31
  • 29 Uitto J, Li Q, Urban Z. The complexity of elastic fibre biogenesis in the skin–a perspective to the clinical heterogeneity of cutis laxa. Exp Dermatol 2013; 22 (02) 88-92
  • 30 Satta J, Haukipuro K, Kairaluoma MI, Juvonen T. Aminoterminal propeptide of type III procollagen in the follow-up of patients with abdominal aortic aneurysms. J Vasc Surg 1997; 25 (05) 909-915
  • 31 Eugster T, Huber A, Obeid T, Schwegler I, Gürke L, Stierli P. Aminoterminal propeptide of type III procollagen and matrix metalloproteinases-2 and -9 failed to serve as serum markers for abdominal aortic aneurysm. Eur J Vasc Endovasc Surg 2005; 29 (04) 378-382
  • 32 Yilmaz MI, Siriopol D, Saglam M. et al. Plasma endocan levels associate with inflammation, vascular abnormalities, cardiovascular events, and survival in chronic kidney disease. Kidney Int 2014; 86 (06) 1213-1220
  • 33 Kali A, Shetty KS. Endocan: a novel circulating proteoglycan. Indian J Pharmacol 2014; 46 (06) 579-583
  • 34 Linhardt RJ, Hileman RE. Dermatan sulfate as a potential therapeutic agent. Gen Pharmacol 1995; 26 (03) 443-451
  • 35 Casu B, Guerrini M, Torri G. Structural and conformational aspects of the anticoagulant and anti-thrombotic activity of heparin and dermatan sulfate. Curr Pharm Des 2004; 10 (09) 939-949
  • 36 Tovar AM, Teixeira LA, Marinho AC, Pinho DA, Silva LF, Mourão PA. The dermatan sulfate-dependent anticoagulant pathway is mostly preserved in aneurysm and in severe atherosclerotic lesions while the heparan sulfate pathway is disrupted. Clin Chim Acta 2011; 412 (11–12): 906-913
  • 37 Di Martino ES, Bohra A, Vande Geest JP, Gupta N, Makaroun MS, Vorp DA. Biomechanical properties of ruptured versus electively repaired abdominal aortic aneurysm wall tissue. J Vasc Surg 2006; 43 (03) 570-576 , discussion 576
  • 38 Vande Geest JP, Sacks MS, Vorp DA. The effects of aneurysm on the biaxial mechanical behavior of human abdominal aorta. J Biomech 2006; 39 (07) 1324-1334
  • 39 Zhang H, Davies KJ, Forman HJ. TGFβ1 rapidly activates Src through a non-canonical redox signaling mechanism. Arch Biochem Biophys 2015; 568: 1-7
  • 40 Sato M, Kawai-Kowase K, Sato H. et al. c-Src and hydrogen peroxide mediate transforming growth factor-beta1-induced smooth muscle cell-gene expression in 10T1/2 cells. Arterioscler Thromb Vasc Biol 2005; 25 (02) 341-347
  • 41 Te Boekhorst V, Friedl P. Plasticity of cancer cell invasion-mechanisms and implications for therapy. Adv Cancer Res 2016; 132: 209-264
  • 42 Huhtinen A, Hongisto V, Laiho A, Löyttyniemi E, Pijnenburg D, Scheinin M. Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells. BMC Syst Biol 2017; 11 (01) 65
  • 43 Yan Y, Ma L, Zhou X. et al. Src inhibition blocks renal interstitial fibroblast activation and ameliorates renal fibrosis. Kidney Int 2016; 89 (01) 68-81
  • 44 Hollenbeck ST, Itoh H, Louie O, Faries PL, Liu B, Kent KC. Type I collagen synergistically enhances PDGF-induced smooth muscle cell proliferation through pp60src-dependent crosstalk between the alpha2beta1 integrin and PDGFbeta receptor. Biochem Biophys Res Commun 2004; 325 (01) 328-337
  • 45 Liu B, Itoh H, Louie O, Kubota K, Kent KC. The role of phospholipase C and phosphatidylinositol 3-kinase in vascular smooth muscle cell migration and proliferation. J Surg Res 2004; 120 (02) 256-265
  • 46 Qian Z, Li Y, Yang H, Chen J, Li X, Gou D. PDGFBB promotes proliferation and migration via regulating miR-1181/STAT3 axis in human pulmonary arterial smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 2018; 315 (06) L965-L976
  • 47 Yang CM, Lin CC, Lee IT. et al. c-Src-dependent transactivation of EGFR mediates CORM-2-induced HO-1 expression in human tracheal smooth muscle cells. J Cell Physiol 2015; 230 (10) 2351-2361
  • 48 Samarakoon R, Higgins SP, Higgins CE, Higgins PJ. TGF-beta1-induced plasminogen activator inhibitor-1 expression in vascular smooth muscle cells requires pp60(c-src)/EGFR(Y845) and Rho/ROCK signaling. J Mol Cell Cardiol 2008; 44 (03) 527-538
  • 49 Liao M, Xu J, Clair AJ, Ehrman B, Graham LM, Eagleton MJ. Local and systemic alterations in signal transducers and activators of transcription (STAT) associated with human abdominal aortic aneurysms. J Surg Res 2012; 176 (01) 321-328