Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation

Abstract Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizyg...

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Autores principales:	L. B. Steffensen, J. Stubbe, J. S. Lindholt, H. C. Beck, M. Overgaard, M. Bloksgaard, F. Genovese, S. Holm Nielsen, M. L. T. Tha, S. K. Bang-Moeller, M. K. T. Hong Lin, J. H. Larsen, D. R. Hansen, G. T. Jones, M. J. Bown, M. A. Karsdal, L. M. Rasmussen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/3d1b5c247947475dacbe108ba6ec5da2
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spelling	oai:doaj.org-article:3d1b5c247947475dacbe108ba6ec5da22021-12-02T16:04:14ZBasement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation10.1038/s41598-021-92303-y2045-2322https://doaj.org/article/3d1b5c247947475dacbe108ba6ec5da22021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-92303-yhttps://doaj.org/toc/2045-2322Abstract Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2 +/− , 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.L. B. SteffensenJ. StubbeJ. S. LindholtH. C. BeckM. OvergaardM. BloksgaardF. GenoveseS. Holm NielsenM. L. T. ThaS. K. Bang-MoellerM. K. T. Hong LinJ. H. LarsenD. R. HansenG. T. JonesM. J. BownM. A. KarsdalL. M. RasmussenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q L. B. Steffensen J. Stubbe J. S. Lindholt H. C. Beck M. Overgaard M. Bloksgaard F. Genovese S. Holm Nielsen M. L. T. Tha S. K. Bang-Moeller M. K. T. Hong Lin J. H. Larsen D. R. Hansen G. T. Jones M. J. Bown M. A. Karsdal L. M. Rasmussen Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation
description	Abstract Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2 +/− , 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.
format	article
author	L. B. Steffensen J. Stubbe J. S. Lindholt H. C. Beck M. Overgaard M. Bloksgaard F. Genovese S. Holm Nielsen M. L. T. Tha S. K. Bang-Moeller M. K. T. Hong Lin J. H. Larsen D. R. Hansen G. T. Jones M. J. Bown M. A. Karsdal L. M. Rasmussen
author_facet	L. B. Steffensen J. Stubbe J. S. Lindholt H. C. Beck M. Overgaard M. Bloksgaard F. Genovese S. Holm Nielsen M. L. T. Tha S. K. Bang-Moeller M. K. T. Hong Lin J. H. Larsen D. R. Hansen G. T. Jones M. J. Bown M. A. Karsdal L. M. Rasmussen
author_sort	L. B. Steffensen
title	Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation
title_short	Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation
title_full	Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation
title_fullStr	Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation
title_full_unstemmed	Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation
title_sort	basement membrane collagen iv deficiency promotes abdominal aortic aneurysm formation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/3d1b5c247947475dacbe108ba6ec5da2
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Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation

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