Spatiotemporal expression and localization of matrix metalloproteinas-9 in a murine model of thoracic aortic aneurysm

Jones, Jeffrey A.; Barbour, John R.; Lowry, Abigail S.; Bouges, Shenikqua; Beck, Christy; McClister, David M.; Mukherjee, Rupak; Ikonomidis, John S.

doi:10.1016/j.jvs.2006.07.042

Cited by 27 publications

(41 citation statements)

References 36 publications

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“…Consistent with previous results from this laboratory demonstrating minimal inflammatory infiltrate through 4-week post-TAA induction, 13 no change in the number of macrophages or neutrophils was observed through 16 weeks. These results support the hypothesis that alterations in the endogenous cellular constituents are responsible for the altered matrix metalloproteinase levels observed during TAA formation.…”

Section: Analysis Of Taa-induced Cellular Constituentssupporting

confidence: 92%

“…The descending thoracic aorta was exposed through a left thoracotomy, and the baseline aortic outer diameter was measured by video micrometry and recorded as described previously. 13 A sponge soaked in 0.5 M calcium chloride was then placed in direct contact with the periadventitial surface for 15 minutes. The chest was closed in layers, and the mice were allowed to recover.…”

Section: Operative Proceduresmentioning

confidence: 99%

“…This observation was consistent with previous studies from our laboratory and others. 13,29 Accordingly, several measures were used to assess changes in the elastic architecture. First, the numbers of unbroken elastic lamellae were quantitated at each time point by direct counting.…”

Section: Analysis Of Taa-induced Structural Changesmentioning

confidence: 99%

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Alterations in Aortic Cellular Constituents during Thoracic Aortic Aneurysm Development

Jones

Beck

Barbour

et al. 2009

The American Journal of Pathology

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The present study tested the hypothesis that changes in the resident endogenous cellular population accompany alterations in aortic collagen and elastin content during thoracic aortic aneurysm (TAA) development in a murine model. Descending thoracic aortas were analyzed at various time points (2, 4, 8, and 16 weeks) post-TAA induction (0.5 M CaCl 2 , 15 minutes). Aortic tissue sections were subjected to histological staining and morphometric analysis for collagen and elastin, as well as immunostaining for cell-type-specific markers to quantify fibroblasts, myofibroblasts, and smoothmuscle cells. Results were compared with reference control mice processed in the same fashion. Aortic dilatation was accompanied by changes in the elastic architecture that included: a decreased number of elastic lamellae (from 6 to 4); altered area fraction of elastin (elevated at 4 weeks and decreased at 16 weeks); and a decreased area between elastic lamellae (minimum reached at 4 weeks). Total collagen content did not change over time. Increased immunoreactivity for fibroblast and myofibroblast markers was observed at 8-and 16-week post-TAA-induction, whereas immunoreactivity for smooth-muscle cell markers peaked at 4 weeks and returned to baseline by 16 weeks. Therefore, this study demonstrated that changes in aortic elastin content were accompanied by the emergence of a subset of fibroblast-derived myofibroblasts whose altered phenotype may play a significant role in TAA development through the enhancement of extracellular matrix proteolysis.

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Section: Analysis Of Taa-induced Cellular Constituentssupporting

confidence: 92%

Section: Operative Proceduresmentioning

confidence: 99%

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Alterations in Aortic Cellular Constituents during Thoracic Aortic Aneurysm Development

Jones

Beck

Barbour

et al. 2009

The American Journal of Pathology

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“…Aortic outer diameter measurements were made as previously described [21]. Paraffin-embedded formalin-fixed aortic tissue sections (4 µm) were stained with hematoxylin and eosin (H&E) for general architecture, Verhoeff-Van Gieson for elastin fibers, and picrosirius red (PSR) for collagen content.…”

Section: Methodsmentioning

confidence: 99%

Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic Aneurysm

et al. 2008

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Objective: Thoracic aortic aneurysms (TAAs) develop by a multifactorial process involving maladaptive signaling pathways that alter the aortic vascular environment. Transforming growth factor-beta (TGF-β) has been implicated in regulating the structure and composition of the extracellular matrix by differential activation of various intracellular signaling pathways. However, whether and to what degree TGF-β signaling contributes to TAA development remains unclear. Accordingly, the hypothesis that alterations in TGF-β signaling occur during aneurysm formation was tested in a murine model of TAA. Methods: TAAs were surgically induced in mice (C57BL/6J) and aortas were analyzed at predetermined time points (1, 2, and 4 weeks post-TAA induction). Quantitative real-time PCR (QPCR) was performed to evaluate the expression of 84 relevant TGF-β superfamily genes, and the protein levels of key signaling intermediates were measured by immunoblotting. Results were compared to unoperated reference control mice. Results: QPCR revealed increased expression of TGF-β superfamily ligands (Gdf-2, -6, -7, Inhba), ligand inhibitors (Bmper, Chrd, Gsc), and transcriptional regulators (Dlx2, Evi1), among other genes (Cdkn2b, Igf1, IL-6). Protein levels of TGF-β receptor_II, Smad2, Smad1/5/8, phospho-Smad1/5/8, and Smurf1 were increased from control values post-TAA induction. Both TGF-β receptor_I and Smad4 were decreased from control values, while ALK-1 levels remained unchanged. Conclusions: These alterations in the TGF-β pathway suggest a mechanism by which primary signaling is switched from a TGF-βR_I/Smad2-dependent response, to an ALK-1/Smad1/5/8 response, representing a significant change in signaling outcome, which may enhance matrix degradation.

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“…Furthermore, in ApoE knockout mice, which presented marked hypercholesterolemia, CA formation was not changed, indicating that hypercholesterolemia, a main risk factor of atherosclerosis, might not be responsible for CA formation (27). MMP-9 is a proteinase with both collagenase and elastase activity, and plays a critical role in both CA (25) and AAA formation (28,29). MMP-2 is another proteinase with both collagenase and elastase activity.…”

Section: Discussionmentioning

confidence: 99%

Role of angiotensin II type 1 receptor in cerebral aneurysm formation in rats

Aoki

Nakagawa²,

Kataoka³

et al. 2009

Int J Mol Med

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Abstract. Cerebral aneurysm (CA) causes catastrophic subarachnoid hemorrhage which is characterized by a high mortality and morbidity rate. CA is a common disease worldwide but to date there is no medical treatment against unruptured CAs. Thus, it is important to study the mechanisms of CA formation. Our previous report demonstrated that chronic inflammatory response in cerebral arterial bifurcation by hemodynamic stress deteriorated arterial walls and formed CA. Therefore, drugs with anti-inflammatory effects might effectively treat CA formation. As renin angiotensin system (RAS) is a major inflammatory cascade and related to various vascular diseases, including aortic aneurysms, the role of angiotensin (Ang) II type 1 receptor might contribute to the progression of CAs. However, in cerebral aneurysmal walls, Ang II type 1 receptor was not up-regulated. In addition, subcutaneously administered Ang II type 1 receptor blocker did not inhibit CA formation, nor inflammation in cerebral aneurysmal walls in rat models at a sub-suppressor dose. These results indicate that RAS might play a less important role in CA formation compared to aortic anuerysms or other vascular diseases. This suggests that there are different mechanisms between the pathogenesis of cereberal and aortic aneurysms.

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Spatiotemporal expression and localization of matrix metalloproteinas-9 in a murine model of thoracic aortic aneurysm

Cited by 27 publications

References 36 publications

Alterations in Aortic Cellular Constituents during Thoracic Aortic Aneurysm Development

Alterations in Aortic Cellular Constituents during Thoracic Aortic Aneurysm Development

Altered Transforming Growth Factor-Beta Signaling in a Murine Model of Thoracic Aortic Aneurysm

Role of angiotensin II type 1 receptor in cerebral aneurysm formation in rats

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