Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection
Frank S. Cikach, … , Eric E. Roselli, Suneel S. Apte
Frank S. Cikach, … , Eric E. Roselli, Suneel S. Apte
Published March 8, 2018
Citation Information: JCI Insight. 2018;3(5):e97167. https://doi.org/10.1172/jci.insight.97167.
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Research Article Vascular biology

Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection

Abstract

Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair.

Authors

Frank S. Cikach, Christopher D. Koch, Timothy J. Mead, Josephine Galatioto, Belinda B. Willard, Kelly B. Emerton, Matthew J. Eagleton, Eugene H. Blackstone, Francesco Ramirez, Eric E. Roselli, Suneel S. Apte

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Figure 4

Aggrecan accumulates in the Fbn1mgR/mgR ascending aorta.

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Aggrecan accumulates in the Fbn1mgR/mgR ascending aorta. The temporal an...
The temporal and spatial distribution of aggrecan and a disintegrin-like and metalloprotease domain with thrombospondin type 1 motifs (ADAMTS) protease-cleaved aggrecan was determined in wild-type mice and Fbn1mgR/mgR mice, a model for severe Marfan syndrome, at various postnatal (P) ages (shown in days). (A) Aggrecan immunofluorescence in wild-type and Fbn1mgR/mgR aortas. Images are representative of staining in n = 3 wild type and n = 3 or 4 (P90) at each time point for Fbn1mgR/mgR mice. Scale bars: 100 μm. (B) Quantification of fluorescence signal in the wild-type (wt) and Fbn1mgR/mgR (mgR) groups represented in A are shown as median with interquartile range. Differences between groups were assessed using the Mann-Whitney U test with JMP Pro software (version 13). n = 3–4. *P ≤ 0.05. (C) Immunofluorescence of the NITEGE neoepitope arising from ADAMTS-cleaved aggrecan in wild-type and Fbn1mgR/mgR aortas. Images representative of staining in n = 3 or 4 (P90) wild-type and n = 3 at each time point for Fbn1mgR/mgR mice. Scale bars: 100 μm. (D) Quantification of fluorescence signal in the experimental groups represented in C shown as median with interquartile range. n = 3–4. *P ≤ 0.05.