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 5

Severe aggrecan accumulation occurs in Fbn1mgR/mgR mice with ascending thoracic aorta dissection/rupture.

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Severe aggrecan accumulation occurs in Fbn1mgR/mgR mice with ascending t...
(A) Aggrecan immunofluorescence in aortas of Fbn1mgR/mgR mice that were euthanized and mice that died from ascending thoracic aorta dissection and/or rupture. The images are representative of aortas from 6 euthanized mice and 5 dissected/ruptured thoracic aortas whose postnatal (P) ages in days are indicated. The lower row contains magnified views of the boxed areas in the upper row. Scale bars: 100 μm; asterisks identify the aortic lumen. (B) Aggrecan is present at high levels at sites of dissection and rupture. Asterisks and arrows denote the aortic lumen and the site of dissection or rupture, respectively. These images are representative of 3 dissected/ruptured aortas where the disruption of the aortic wall was visualized histologically. (C) Quantification of aggrecan immunofluorescence in euthanized P60 and P90 Fbn1mgR/mgR mice (n = 3 of each, total n = 6) and Fbn1mgR/mgR mice older than P45 who died with ascending aortic dissection or rupture (n = 5, ages P52, P60, P64, P64, and P80). Each data point represents an independent biological replicate. Differences between groups were assessed using the Mann-Whitney U test with JMP Pro software (version 13). Bars represent the median with interquartile range. **P ≤ 0.01.