Inflammatory cell infiltrates, hypoxia, vascularization, pentraxin 3 and osteoprotegerin in abdominal aortic aneurysms – A quantitative histological study

English version

Autoři: Tereza Blassova ^aff001; Zbynek Tonar ^aff001; Petr Tomasek ^aff001; Petr Hosek ^aff001; Ivana Hollan ^aff002; Vladislav Treska ^aff004; Jiri Molacek ^aff004
Působiště autorů: Department of Histology and Embryology and Biomedical Centre, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic ^aff001; Hospital for Rheumatic Diseases, Lillehammer, Norway ^aff002; Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, United States of America ^aff003; Department of Vascular Surgery, University Hospital in Pilsen, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic ^aff004
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pone.0224818

Souhrn

Information about the tissue characteristics of abdominal aortic aneurysms (AAAs), some of which may be reflected in the serum, can help to elucidate AAA pathogenesis and identify new AAA biomarkers. This information would be beneficial not only for diagnostics and follow-up but also for potential therapeutic intervention. Therefore, the aim of our study was to compare the expression of structural proteins, immune factors (T and B lymphocytes, macrophages, neutrophils and pentraxin 3 (PTX3)), osteoprotegerin (OPG), microvessels and hypoxic cells in AAA and nonaneurysmal aortic walls. We examined specimens collected during surgery for AAA repair (n = 39) and from the abdominal aortas of kidney donors without AAA (n = 8). Using histochemical and immunohistochemical methods, we quantified the areas positive for smooth muscle actin, desmin, elastin, collagen, OPG, CD3, CD20, MAC387, myeloperoxidase, PTX3, and hypoxia-inducible factor 1-alpha and the density of CD31-positive microvessels. AAA samples contained significantly less actin, desmin, elastin and OPG, more collagen, macrophages, neutrophils, T lymphocytes, B lymphocytes, hypoxic cells and PTX3, and a greater density of vasa vasorum (VV) than those in non-AAA samples. Hypoxia positively correlated with actin and negatively correlated with collagen. Microvascular density was related to inflammatory cell infiltrates, hypoxia, PTX3 expression and AAA diameter. The lower OPG expression in AAAs supports the notion of its protective role in AAA remodeling. AAA contained altered amounts of structural proteins, implying reduced vascular elasticity. PTX3 was upregulated in AAA and colocalized with inflammatory infiltrates. This evidence supports further evaluation of PTX3 as a candidate marker of AAA. The presence of aortic hypoxia, despite hypervascularization, suggests that hypoxia-induced neoangiogenesis may play a role in AAA pathogenesis. VV angiogenesis of the AAA wall increases its vulnerability.

Klíčová slova:

Inflammation – B cells – Macrophages – Hypoxia – Immunohistochemistry techniques – Neutrophils – Histology – Medical hypoxia

Zdroje

1. Kühnl A, Erk A, Trenner M, Salvermoser M, Schmid V, Eckstein H-H. Incidence, Treatment and Mortality in Patients with Abdominal Aortic Aneurysms: An Analysis of Hospital Discharge Data from 2005–2014. Dtsch Aerzteblatt Online. 2017; doi: 10.3238/arztebl.2017.0391 28655374

2. Eberlová L, Tonar Z, Witter K, Křížková V, Nedorost L, Korabečná M, et al. Asymptomatic Abdominal Aortic Aneurysms Show Histological Signs of Progression: a Quantitative Histochemical Analysis. Pathobiol J Immunopathol Mol Cell Biol. 2013;80: 11–23. doi: 10.1159/000339304 22797551

3. Billaud M, Hill JC, Richards TD, Gleason TG, Phillippi JA. Medial Hypoxia and Adventitial Vasa Vasorum Remodeling in Human Ascending Aortic Aneurysm. Front Cardiovasc Med. 2018;5. doi: 10.3389/fcvm.2018.00124 30276199

4. Rodella LF, Rezzani R, Bonomini F, Peroni M, Cocchi MA, Hirtler L, et al. Abdominal Aortic Aneurysm and Histological, Clinical, Radiological Correlation. Acta Histochem. 2016;118: 256–262. doi: 10.1016/j.acthis.2016.01.007 26858185

5. Tanaka H, Zaima N, Sasaki T, Sano M, Yamamoto N, Saito T, et al. Hypoperfusion of the Adventitial Vasa Vasorum Develops an Abdominal Aortic Aneurysm. PloS One. 2015;10: e0134386. doi: 10.1371/journal.pone.0134386 26308526

6. Reeps C, Pelisek J, Seidl S, Schuster T, Zimmermann A, Kuehnl A, et al. Inflammatory Infiltrates and Neovessels Are Relevant Sources of MMPs in Abdominal Aortic Aneurysm Wall. Pathobiol J Immunopathol Mol Cell Biol. 2009;76: 243–252. doi: 10.1159/000228900 19816084

7. Cieślik P, Hrycek A. Long Pentraxin 3 (PTX3) in the Light of Its Structure, Mechanism of Action and Clinical Implications. Autoimmunity. 2012;45: 119–128. doi: 10.3109/08916934.2011.611549 21988562

8. Bonacina F, Baragetti A, Catapano AL, Norata GD. Long Pentraxin 3: Experimental and Clinical Relevance in Cardiovascular Diseases. Mediators Inflamm. 2013;2013: 1–10. doi: 10.1155/2013/725102 23690668

9. Yigit S, Sari S, Canbolat IP, Arat Ozkan A, Ersanli MK, Gurmen T. Pentraxin-3 a Novel Biomarker for Predicting Coronary Artery Disease. Eur Heart J. 2013;34: P3108–P3108. doi: 10.1093/eurheartj/eht309.P3108

10. Buda V, Andor M, Tomescu MC, Cristescu C, Voicu M, Citu I, et al. P2637ACE Inhibitors and ARBs Decrease More Powerful the PTX-3 Plasma Levels of Hypertensive Patients with Endothelial Dysfunction Compared with Other Anti-Hypertensive Drugs, in a Chronic Treatment. Eur Heart J. 2017;38. doi: 10.1093/eurheartj/ehx502.P2637

11. Nakamura A, Miura S, Shiga Y, Norimatsu K, Miyase Y, Suematsu Y, et al. Is Pentraxin 3 a Biomarker, a Player, or Both in the Context of Coronary Atherosclerosis and Metabolic Factors? Heart Vessels. 2015;30: 752–761. doi: 10.1007/s00380-014-0553-0 25048680

12. Norata GD, Garlanda C, Catapano AL. The Long Pentraxin PTX3: A Modulator of the Immunoinflammatory Response in Atherosclerosis and Cardiovascular Diseases. Trends Cardiovasc Med. 2010;20: 35–40. doi: 10.1016/j.tcm.2010.03.005 20656213

13. Koole D, Hurks R, Schoneveld A, Vink A, Golledge J, Moran CS, et al. Osteoprotegerin Is Associated with Aneurysm Diameter and Proteolysis in Abdominal Aortic Aneurysm Disease. Arterioscler Thromb Vasc Biol. 2012;32: 1497–1504. doi: 10.1161/ATVBAHA.111.243592 22516062

14. Callegari A, Coons ML, Ricks JL, Rosenfeld ME, Scatena M. Increased Calcification in Osteoprotegerin-Deficient Smooth Muscle Cells: Dependence on Receptor Activator of NF-κB Ligand and Interleukin 6. J Vasc Res. 2014;51: 118–131. doi: 10.1159/000358920 24642764

15. Morony S, Tintut Y, Zhang Z, Cattley RC, Van G, Dwyer D, et al. Osteoprotegerin Inhibits Vascular Calcification without Affecting Atherosclerosis in Ldlr(-/-) Mice. Circulation. 2008;117: 411–420. doi: 10.1161/CIRCULATIONAHA.107.707380 18172035

16. Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K, et al. Serum Osteoprotegerin Levels Are Associated with the Presence and Severity of Coronary Artery Disease. Circulation. 2002;106: 1192–1194. doi: 10.1161/01.cir.0000031524.49139.29 12208791

17. Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J. Association of Osteoprotegerin With Human Abdominal Aortic Aneurysm Progression. Circulation. 2005;111: 3119–3125. doi: 10.1161/CIRCULATIONAHA.104.464727 15939823

18. Bennett BJ, Scatena M, Kirk EA, Rattazzi M, Varon RM, Averill M, et al. Osteoprotegerin Inactivation Accelerates Advanced Atherosclerotic Lesion Progression and Calcification in Older ApoE-/- Mice. Arterioscler Thromb Vasc Biol. 2006;26: 2117–2124. doi: 10.1161/01.ATV.0000236428.91125.e6 16840715

19. Bumdelger B, Kokubo H, Kamata R, Fujii M, Yoshimura K, Aoki H, et al. Osteoprotegerin Prevents Development of Abdominal Aortic Aneurysms. PloS One. 2016;11: e0147088. doi: 10.1371/journal.pone.0147088 26783750

20. Bancroft JD, Gamble M. Theory and Practice of Histological Techniques. [Edinburgh]: Churchill Livingstone; 2008.

21. Kocová J. Overall Staining of Connective Tissue and the Muscular Layer of Vessels. Folia Morphol. 1970;18: 293–295.

22. Rich L, Whittaker P. Collagen and Picrosirius Red Staining: a Polarized Light Assessment of Fibrillar Hue and Spatial Distribution. Braz J Morphol Sci. 2005;2005: 97–104.

23. Kubíková T, Kochová P, Brázdil J, Špatenka J, Burkert J, Králíčková M, et al. The Composition and Biomechanical Properties of Human Cryopreserved Aortas, Pulmonary Trunks, and Aortic and Pulmonary Cusps. Ann Anat—Anat Anz. 2017;212: 17–26. doi: 10.1016/j.aanat.2017.03.004 28434910

24. Tonar Z, Tomášek P, Loskot P, Janáček J, Králíčková M, Witter K. Vasa Vasorum in the Tunica Media and Tunica Adventitia of the Porcine Aorta. Ann Anat—Anat Anz. 2016;205: 22–36. doi: 10.1016/j.aanat.2016.01.008 26844625

25. Houdek K, Moláček J, Třeška V, Křížková V, Eberlová L, Boudová L, et al. Focal Histopathological Progression of Porcine Experimental Abdominal Aortic Aneurysm is Mitigated by Atorvastatin. Int Angiol J Int Union Angiol. 2013;32: 291–306.

26. Mouton PR. Principles and Practices of Unbiased Stereology: an Introduction for Bioscientists. Baltimore: Johns Hopkins University Press; 2002.

27. Tonar Z, Kubíková T, Prior C, Demjén E, Liška V, Králíčková M, et al. Segmental and Age Differences in the Elastin Network, Collagen, and Smooth Muscle Phenotype in the Tunica Media of the Porcine Aorta. Ann Anat Anat Anz Off Organ Anat Ges. 2015;201: 79–90. doi: 10.1016/j.aanat.2015.05.005 26232584

28. Tonar Z, Egger GF, Witter K, Wolfesberger B. Quantification of Microvessels in Canine Lymph Nodes. Microsc Res Tech. 2008;71: 760–772. doi: 10.1002/jemt.20619 18615685

29. Howard V, Reed MG. Unbiased Stereology: Three-Dimensional Measurement in Microscopy. Liverpool: QTP; 2010.

30. Witter K, Tonar Z, Schöpper H. How many Layers has the Adventitia?—Structure of the Arterial Tunica Externa Revisited. Anat Histol Embryol. 2017;46: 110–120. doi: 10.1111/ahe.12239 27282337

31. Holmes DR, Liao S, Parks WC, Thompson RW. Medial Neovascularization in Abdominal aortic Aneurysms: a Histopathologic Marker of Aneurysmal Degeneration with Pathophysiologic Implications. J Vasc Surg. 1995;21: 761–771; discussion 771–772. doi: 10.1016/s0741-5214(05)80007-2 7539511

32. Tanaka H, Unno N, Yata T, Kugo H, Zaima N, Sasaki T, et al. Creation of a Rodent Model of Abdominal Aortic Aneurysm by Blocking Adventitial Vasa Vasorum Perfusion. J Vis Exp. 2017; doi: 10.3791/55763 29155740

33. Vorp DA, Lee PC, Wang DH, Makaroun MS, Nemoto EM, Ogawa S, et al. Association of Intraluminal Thrombus in Abdominal Aortic Aneurysm with Local Hypoxia and Wall Weakening. J Vasc Surg. 2001;34: 291–299. doi: 10.1067/mva.2001.114813 11496282

34. Tanaka H, Zaima N, Sasaki T, Hayasaka T, Goto-Inoue N, Onoue K, et al. Adventitial Vasa Vasorum Arteriosclerosis in Abdominal Aortic Aneurysm. PloS One. 2013;8: e57398. doi: 10.1371/journal.pone.0057398 23460850

35. Popescu MR, Butcovan D, Folescu R, Motoc A, Zamfir CL. Thoracic Aorta Dissection—Assessment of Aortic Adventitia Involvement. Rom J Leg Med. 2013;21: 207–2014. doi: 0.4323/rjlm.2013.207

36. Gäbel G, Northoff BH, Weinzierl I, Ludwig S, Hinterseher I, Wilfert W, et al. Molecular Fingerprint for Terminal Abdominal Aortic Aneurysm Disease. J Am Heart Assoc. 2017;6. doi: 10.1161/JAHA.117.006798 29191809

37. Tsai S-H, Huang P-H, Hsu Y-J, Peng Y-J, Lee C-H, Wang J-C, et al. Inhibition of Hypoxia Inducible Factor-1α Attenuates Abdominal Aortic Aneurysm Progression through the Down-Regulation of Matrix Metalloproteinases. Sci Rep. 2016;6: 28612. doi: 10.1038/srep28612 27363580

38. Docherty CK, Nilsen M, MacLean MR. Influence of 2-Methoxyestradiol and Sex on Hypoxia-Induced Pulmonary Hypertension and Hypoxia-Inducible Factor-1-α. J Am Heart Assoc. 2019;8: e011628. doi: 10.1161/JAHA.118.011628 30819028

39. Sawada H, Naito Y, Oboshi M, Iwasaku T, Morisawa D, Okuhara Y, et al. Pentraxin 3 Expression in Human Abdominal Aortic Aneurysm. Circulation. 2014;2014: A15060.

40. Sawada H, Naito Y, Oboshi M, Soyama Y, Nishimura K, Eguchi A, et al. Increment of Pentraxin3 Expression in Abdominal Aortic Aneurysm. Int J Cardiol. 2015;195: 281–282. doi: 10.1016/j.ijcard.2015.05.177 26056957

41. Molacek J, Treska V, Zeithaml J, Hollan I, Topolcan O, Pecen L, et al. Blood Biomarker Panel Recommended for Personalized Prediction, Prognosis, and Prevention of Complications Associated with Abdominal Aortic Aneurysm. EPMA J. 2019;10: 125–135. doi: 10.1007/s13167-019-00173-2 31258818

42. Arao K, Fujiwara T, Taniguchi Y, Jinnouchi H, Sasai H, Matsumoto M, et al. Implications of Pentraxin 3 Levels in Patients with Acute Aortic Dissection. Heart Vessels. 2015;30: 211–217. doi: 10.1007/s00380-014-0470-2 24474442

43. Folsom Aaron R., Yao Lu, Alonso Alvaro, Lutsey Pamela L., Missov Emil, Lederle Frank A., et al. Circulating Biomarkers and Abdominal Aortic Aneurysm Incidence. Circulation. 2015;132: 578–585. doi: 10.1161/CIRCULATIONAHA.115.016537 26085454

44. Henriksson AE, Lindqvist M, Sihlbom C, Bergström J, Bylund D. Identification of Potential Plasma Biomarkers for Abdominal Aortic Aneurysm Using Tandem Mass Tag Quantitative Proteomics. Proteomes. 2018;6. doi: 10.3390/proteomes6040043 30340394

45. Moris D, Mantonakis E, Avgerinos E, Makris M, Bakoyiannis C, Pikoulis E, et al. Novel Biomarkers of Abdominal Aortic Aneurysm Disease: Identifying Gaps and Dispelling Misperceptions. BioMed Res Int. 2014;2014: 1–13. doi: 10.1155/2014/925840 24967416

46. Urbonavicius S, Urbonaviciene G, Honoré B, Henneberg EW, Vorum H, Lindholt JS. Potential Circulating Biomarkers for Abdominal Aortic Aneurysm Expansion and Rupture—a Systematic Review. Eur J Vasc Endovasc Surg. 2008;36: 273–280. doi: 10.1016/j.ejvs.2008.05.009 18639476

47. Fornai F, Carrizzo A, Forte M, Ambrosio M, Damato A, Ferrucci M, et al. The Inflammatory Protein Pentraxin 3 in Cardiovascular Disease. Immun Ageing A. 2016;13: 25. doi: 10.1186/s12979-016-0080-1 27559355

48. Cabiati M, Svezia B, Verde A, Caselli C, Del Ry S. P3401Pentraxin 3, a Novel Inflammatory Marker in Heart Failure Patients: Its Expression in Circulating Leukocytes as a Function of Clinical Severity. Eur Heart J. 2017;38. doi: 10.1093/eurheartj/ehx504.P3401

49. Liu H, Guan S, Fang W, Yuan F, Zhang M, Qu X. Associations Between Pentraxin 3 and Severity of Coronary Artery Disease. BMJ Open. 2015;5: e007123. doi: 10.1136/bmjopen-2014-007123 25854969

50. Kinoshita M, Yokote K, Arai H, Iida M, Ishigaki Y, Ishibashi S, et al. Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2017. J Atheroscler Thromb. 2018;25: 846–984. doi: 10.5551/jat.GL2017 30135334

51. Armstrong PJ, Johanning JM, Calton WC, Delatore JR, Franklin DP, Han DC, et al. Differential Gene Expression in Human Abdominal Aorta: Aneurysmal versus Occlusive Disease. J Vasc Surg. 2002;35: 346–14. doi: 10.1067/mva.2002.121071 11854734

52. Patel R, Sweeting MJ, Powell JT, Greenhalgh RM. Endovascular Versus Open Repair of Abdominal Aortic Aneurysm in 15-years’ Follow-up of the UK Endovascular Aneurysm Repair Trial 1 (EVAR Trial 1): a Randomised Controlled Trial. The Lancet. 2016;388: 2366–2374. doi: 10.1016/S0140-6736(16)31135-7

Inflammatory cell infiltrates, hypoxia, vascularization, pentraxin 3 and osteoprotegerin in abdominal aortic aneurysms – A quantitative histological study

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Zdroje

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