Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection
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
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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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 2

Aggrecan and versican accumulate in human ascending thoracic aortic aneurysm and dissection (TAAD).

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Aggrecan and versican accumulate in human ascending thoracic aortic aneu...
(A) Aggrecan (red) and versican (green) accumulate primarily within the aortic tunica media (M). A and I indicate the aortic adventitia and intima, respectively. Images in columns 2–4 represent higher magnification views of the areas contained within the white boxes in the left-hand column. LDS, Loeys-Dietz syndrome. Scale bars: 200 μm. The images are representative of 6 control and 20 TAAD cases. (B) Intense aggrecan and versican staining is seen in areas of medial degeneration in a case of idiopathic TAAD (left-hand panels) and Marfan syndrome (right-hand panels), identified here as regions with fragmented or absent elastic fibers (green) and few smooth muscle cells (nuclei stained blue) in TAAD aortas. The images are representative of 20 TAAD cases. Scale bars: 200 μm. (C) Quantification of aggrecan and versican within medial degeneration lesions. Representative areas of aggrecan and versican staining were quantified for control samples. 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. Aggrecan: n = 4 control, n = 19 TAAD. Versican: n = 4 control, n = 20 TAAD. **P ≤ 0.01.