MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This st...

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Autores principales:	Bartosz Pilecki, Paulo V. S. D. de Carvalho, Katrine L. Kirketerp-Møller, Anders Schlosser, Karin Kejling, Magdalena Dubik, Nicklas P. Madsen, Jane Stubbe, Pernille B. L. Hansen, Thomas L. Andersen, Jesper B. Moeller, Niels Marcussen, Vasco Azevedo, Svend Hvidsten, Christina Baun, Guo-Ping Shi, Jes S. Lindholt, Grith L. Sorensen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	abdominal aortic aneurysm extracellular matrix inflammation macrophage matrix metalloproteinases Diseases of the circulatory (Cardiovascular) system RC666-701
Acceso en línea:	https://doaj.org/article/eb8cd3b728a9421dbd73188ffc0b98f5
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spelling	oai:doaj.org-article:eb8cd3b728a9421dbd73188ffc0b98f52021-11-05T10:32:07ZMFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity2297-055X10.3389/fcvm.2021.764337https://doaj.org/article/eb8cd3b728a9421dbd73188ffc0b98f52021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fcvm.2021.764337/fullhttps://doaj.org/toc/2297-055XObjective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.Bartosz PileckiPaulo V. S. D. de CarvalhoPaulo V. S. D. de CarvalhoPaulo V. S. D. de CarvalhoKatrine L. Kirketerp-MøllerAnders SchlosserKarin KejlingMagdalena DubikNicklas P. MadsenJane StubbePernille B. L. HansenPernille B. L. HansenThomas L. AndersenThomas L. AndersenJesper B. MoellerJesper B. MoellerNiels MarcussenVasco AzevedoSvend HvidstenChristina BaunGuo-Ping ShiJes S. LindholtGrith L. SorensenFrontiers Media S.A.articleabdominal aortic aneurysmextracellular matrixinflammationmacrophagematrix metalloproteinasesDiseases of the circulatory (Cardiovascular) systemRC666-701ENFrontiers in Cardiovascular Medicine, Vol 8 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	abdominal aortic aneurysm extracellular matrix inflammation macrophage matrix metalloproteinases Diseases of the circulatory (Cardiovascular) system RC666-701
spellingShingle	abdominal aortic aneurysm extracellular matrix inflammation macrophage matrix metalloproteinases Diseases of the circulatory (Cardiovascular) system RC666-701 Bartosz Pilecki Paulo V. S. D. de Carvalho Paulo V. S. D. de Carvalho Paulo V. S. D. de Carvalho Katrine L. Kirketerp-Møller Anders Schlosser Karin Kejling Magdalena Dubik Nicklas P. Madsen Jane Stubbe Pernille B. L. Hansen Pernille B. L. Hansen Thomas L. Andersen Thomas L. Andersen Jesper B. Moeller Jesper B. Moeller Niels Marcussen Vasco Azevedo Svend Hvidsten Christina Baun Guo-Ping Shi Jes S. Lindholt Grith L. Sorensen MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity
description	Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.
format	article
author	Bartosz Pilecki Paulo V. S. D. de Carvalho Paulo V. S. D. de Carvalho Paulo V. S. D. de Carvalho Katrine L. Kirketerp-Møller Anders Schlosser Karin Kejling Magdalena Dubik Nicklas P. Madsen Jane Stubbe Pernille B. L. Hansen Pernille B. L. Hansen Thomas L. Andersen Thomas L. Andersen Jesper B. Moeller Jesper B. Moeller Niels Marcussen Vasco Azevedo Svend Hvidsten Christina Baun Guo-Ping Shi Jes S. Lindholt Grith L. Sorensen
author_facet	Bartosz Pilecki Paulo V. S. D. de Carvalho Paulo V. S. D. de Carvalho Paulo V. S. D. de Carvalho Katrine L. Kirketerp-Møller Anders Schlosser Karin Kejling Magdalena Dubik Nicklas P. Madsen Jane Stubbe Pernille B. L. Hansen Pernille B. L. Hansen Thomas L. Andersen Thomas L. Andersen Jesper B. Moeller Jesper B. Moeller Niels Marcussen Vasco Azevedo Svend Hvidsten Christina Baun Guo-Ping Shi Jes S. Lindholt Grith L. Sorensen
author_sort	Bartosz Pilecki
title	MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity
title_short	MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity
title_full	MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity
title_fullStr	MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity
title_full_unstemmed	MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity
title_sort	mfap4 deficiency attenuates angiotensin ii-induced abdominal aortic aneurysm formation through regulation of macrophage infiltration and activity
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/eb8cd3b728a9421dbd73188ffc0b98f5
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MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity

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