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Vascular remodelling and circulating basement membrane fragments in abdominal aortic aneurysm
Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

An abdominal aortic aneurysm (AAA) is a degenerative disease, characterized by advanced inflammation and extracellular matrix (ECM) remodelling. Enhanced protease activity mediated by cytokines results in the degradation of ECM proteins, leading to the generation of different bioactive fragments. Some of these generated fragments are released from the vascular basement membrane (VBM), a highly specialized ECM. VBM provides mechanical and structural stability and regulates many important cellular functions of the vascular system. Type IV and XVIII collagens are two structural proteins in VBM, with crucial roles in maintaining of the VBM integrity and vascular architecture. Circulating levels of type IV and XVIII collagen fragments are found physiologically, but have also been associated with many diseases. Remodelling of VBM and expression of its components has not been as well studied in AAA as that of the interstitial ECM.

Here we investigate these VBM collagens, their expression and possible association with aortic diameter and expansion rate in individuals with an AAA in comparison with different control groups. Further we study whether there is a link between the circulating VBM collagen fragments and several inflammatory markers, all highly involved in AAA pathogenesis. Lastly, we study the impact of surgical intervention on plasma levels of VBM collagens in patients treated by either open surgical repair (OSR) or endovascular aortic aneurysm repair (EVAR).

Methods: Circulating levels of type IV and XVIII collagen fragments were analysed in individuals with an AAA and compared with healthy controls and patients with peripheral artery disease (paper I). A possible association between VBM collagen fragments and the aortic diameter and expansion was studied in a large population-based cohort of 615 men stratified into three aortic diameter groups based on initial maximum aortic diameter (paper II). Furthermore, 159 individuals were followed up over time with repeated measurements of aortic diameter and blood samples. The follow up cohort were divided into two subgroups based on expansion rate of AAA. Moreover, the location of VBM collagens in tissue from aortic wall in individuals with an AAA was characterized and the expression pattern was compared with normal aorta (paper II). In paper III, the association between the plasma levels of VBM collagens and inflammatory markers; IL-1 (IL-1α and IL-1β), IL-6, IL-8, TNF-α INF-γ and hs-CRP were studied in same cohort as paper II. Finally, the effect of surgical intervention on circulating levels of VBM collagen fragments was investigated in AAA patients who had undegone either OSR or EVAR by comparison of plasma levels before and after AAA repair.

Ultrasound technique was used for measurements of aortic diameter (paper I, II, III and IV). Analysis of circulating VBM collagens and inflammatory markers were performed by ELISA-assay (Paper I, II, III and IV) and Multiplex-assays, respectively (paper III). Aortic wall tissues were analysed by haematoxylin and eosin (H&E) and immunofluorescence staining (Paper II).

Results: There were significantly increased plasma levels of VBM collagen fragments in individuals with an AAA, compared with healthy controls and individulas with a peripheral artery disease (PAD), (Paper I). The levels of type IV collagen in AAA patients did not differ from the group with PAD, and there were no significant differences between the control groups regarding plasma levels of both VBM collagen fragments (Paper I). The increased levels of VBM collagen fragments were significantly associated with aortic diameter with highest levels in the group with an AAA (Paper II). Altered expression of the VBM collagens and fragmentation of elastic fibres were observed in tissue from AAA patients (Paper II). A significant association between the levels of pro-inflammatory cytokines IL-6 and IL-8, and VBM collagens was found. Additionally, there were a significant association between the plasma levels of IL-8, TNF-α and hs-CRP and an AAA (Paper III). Aneurysms with faster expansion rate had significantly higher levels of IL-6, IL-1β, and type XVIII/endostatin collagen. Additionally, IL-6, type XVIII/endostatin collagen and baseline-aortic diameter were significantly associated with expansion rate (Paper III). AAA repair was associated with changes in plasma levels of VBM collagens (Paper IV).

Conclusion: Circulating levels of VBM collagens were increased in patients with an AAA, and significantly associated with aortic diameter and expansion rate. The expression of VBM collagens was altered in AAA tissue compared with normal aorta. In addition, plasma levels of several inflammatory markers were associated as with VBM collagens, aortic diameter and expansion rate. The levels of both VBM collagens were altered at short and long time after AAA repair. 

Place, publisher, year, edition, pages
Umeå: Umeå Universitet , 2019. , p. 77
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2012
Keywords [en]
AAA, extracellular matrix, vascular remodelling, collagen, inflammation
National Category
Surgery
Research subject
Surgery
Identifiers
URN: urn:nbn:se:umu:diva-156532ISBN: 978-91-7855-028-9 (print)OAI: oai:DiVA.org:umu-156532DiVA, id: diva2:1289733
Public defence
2019-03-15, Hörsal B, byggnad 1B, 9 tr., Norrlands universitetssjukhus, Umeå, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2019-02-21 Created: 2019-02-18 Last updated: 2019-02-19Bibliographically approved
List of papers
1. Increased circulating levels of basement-membrane components in patients with abdominal aortic aneurysms: A Pilot Study
Open this publication in new window or tab >>Increased circulating levels of basement-membrane components in patients with abdominal aortic aneurysms: A Pilot Study
2011 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 42, no 4, p. 484-487Article in journal (Refereed) Published
Abstract [en]

Aim: The decision for abdominal aortic aneurysm (AM) repair is based on aneurysm size. However, smaller aneurysms can rupture, while larger ones can remain stable. New variables and markers are needed to better select patients at high rupture risk. The study was done to analyse if AAA patients have increased levels of circulating basement-membrane (BM) fragments.

Design: Circulating levels of BM components type IV and XVIII collagen were measured by enzyme-linked immunosorbent assay (ELISA) in 10 patients with AAA, nine patients with peripheral artery disease (PAD) and 10 healthy controls (CON).

Results: AAA patients had significantly increased levels of type IV and XVIII collagen compared with CON (134.0 +/- 24.8 ng ml(-1) vs. 104.5 +/- 16.4 ng ml(-1); p = 0.005 and 149.0 +/- 56.9 ng ml(-1) vs. 59.6 +/- 8.7 ng ml(-1); p < 0.001, respectively). The PAD patients did not have significantly increased levels of these fragments when compared with CON. In addition, the AAA patients had significantly increased level of type XVIII collagen (149.0 +/- 56.9 ng ml(-1) vs. 58.3 +/- 25.4 ng/ml(-1); p < 0.01) when compared with the PAD group.

Conclusion: Based on this preliminary analysis of a small number of subjects, patients with AAA had significantly increased levels of circulating BM components. BM fragments should be studied further to establish their potential role as biomarkers for AAA.

Place, publisher, year, edition, pages
London: Grune & Stratton, 2011
Keywords
Aortic aneurysm, Collagen, Biomarker, Basement membrane
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-49567 (URN)10.1016/j.ejvs.2011.05.021 (DOI)000296042600016 ()
Available from: 2011-11-22 Created: 2011-11-14 Last updated: 2019-02-18Bibliographically approved
2. Circulating Vascular Basement Membrane Fragments are Associated with the Diameter of the Abdominal Aorta and Their Expression Pattern is Altered in AAA Tissue
Open this publication in new window or tab >>Circulating Vascular Basement Membrane Fragments are Associated with the Diameter of the Abdominal Aorta and Their Expression Pattern is Altered in AAA Tissue
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2018 (English)In: European Journal of Vascular and Endovascular Surgery, ISSN 1078-5884, E-ISSN 1532-2165, Vol. 56, no 1, p. 110-118Article in journal (Refereed) Published
Abstract [en]

Objective: Abdominal aortic aneurysm (AAA) is characterised by enhanced proteolytic activity, and extracellular matrix (ECM) remodelling in the vascular wall. Type IV and XVIII collagen/endostatin are structural proteins in vascular basement membrane (VBM), a specialised ECM structure. Here the association between plasma levels of these collagens with the aortic diameter and expansion rate is studied, and their expression in aortic tissue characterised. Methods: This was a retrospective population based cohort study. Type IV and XVIII collagen/endostatin were analysed in plasma by ELISA assay in 615 men, divided into three groups based on the aortic diameter: 1) normal aorta <= 25 mm, 2) sub-aneurysmal aorta (SAA) 26-29 mm, and 3) AAA >= 30 mm. Follow up data were available for 159 men. The association between collagen levels and aortic diameter at baseline, and with the expansion rate at follow up were analysed in ordinal logistic regression and linear regression models, controlling for common confounding factors. Tissue expression of the collagens was analysed in normal aorta (n = 6) and AAA (n = 6) by immunofluorescence. Results: Plasma levels of type XVIII collagen/endostatin (136 ng/mL [SD 29] in individuals with a normal aorta diameter, 154 ng/ml [SD 45] in SAA, and 162 ng/ml [SD 46] in AAA; p = .001) and type IV collagen (105 ng/mL [SD 42] normal aorta, 124 ng/ml [SD 46] SAA, and 127 ng/ml [SD 47] AAA; p = .037) were associated with a larger aortic diameter. A significant association was found between the baseline levels of type XVIII/endostatin and the aortic expansion rate (p = .035), but in the multivariable model, only the initial aortic diameter remained significantly associated with expansion (p = .005). Altered expression patterns of both collagens were observed in AAA tissue. Conclusion: Plasma levels of circulating type IV and XVIII collagen/endostatin increase with AAA diameter. The expression pattern of VBM proteins is altered in the aneurysm wall.

Place, publisher, year, edition, pages
Saunders Elsevier, 2018
Keywords
Abdominal aortic aneurysm, Collagen, Basement membrane, Extracellular matrix, Circulation
National Category
Surgery
Identifiers
urn:nbn:se:umu:diva-152282 (URN)10.1016/j.ejvs.2018.03.002 (DOI)000444270700019 ()29656960 (PubMedID)
Funder
Västerbotten County Council, VLL-582791Västerbotten County Council, VLL-680121Västerbotten County Council, VLL-764621Swedish Research Council, K2013-64X-2040607-3Swedish Heart Lung Foundation, 2012-0353
Available from: 2018-10-01 Created: 2018-10-01 Last updated: 2019-02-18Bibliographically approved
3. Association of inflammatory cytokines to vascular wall remodelling and the aortic diameter
Open this publication in new window or tab >>Association of inflammatory cytokines to vascular wall remodelling and the aortic diameter
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-156522 (URN)
Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-02-19
4. Effect of aortic aneurysm treatment on circulating levels of vascular basement membrane fragments: a pilot study
Open this publication in new window or tab >>Effect of aortic aneurysm treatment on circulating levels of vascular basement membrane fragments: a pilot study
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Surgery
Research subject
Surgery
Identifiers
urn:nbn:se:umu:diva-156523 (URN)
Available from: 2019-02-18 Created: 2019-02-18 Last updated: 2019-02-19

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