The role of selected metalloproteinases and some genetic factors in the pathogenesis of abdominal aortic aneurysm

AbstractAbdominal aortic aneurysm (AAA) disease is characterized by an asymptomatic, permanent, focal dilatation of the abdominal aorta progressing towards rupture, which confers significant mortality. Patient management and surgical decisions rely on aortic diameter measurements via abdominal ultrasound surveillance. However, AAA rupture can occur at small diameters or may never occur at large diameters, implying that anatomical size is not necessarily a sufficient indicator. Molecular imaging may help identify high-risk patients through AAA evaluation independent of aneurysm size, and there is the question of the potential role of positron emission tomography (PET) and emerging role of novel radiotracers for AAA. Therefore, this review summarizes PET studies conducted in the last 10 years and discusses the usefulness of PET radiotracers for AAA risk stratification. The most frequently reported radiotracer was [18F]fluorodeoxyglucose, indicating inflammatory activity and reflecting the biomechanical properties of AAA. Emerging radiotracers include [18F]-labeled sodium fluoride, a calcification marker, [64Cu]DOTA-ECL1i, an indicator of chemokine receptor type 2 expression, and [18F]fluorothymidine, a marker of cell proliferation. For novel radiotracers, preliminary trials in patients are warranted before their widespread clinical implementation. AAA rupture risk is challenging to evaluate; therefore, clinicians may benefit from PET-based risk assessment to guide patient management and surgical decisions.

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The Role of Geometric Parameters in the Prediction of Abdominal Aortic Aneurysm Wall Stress

European Journal of Vascular and Endovascular Surgery ◽

10.1016/j.ejvs.2009.09.026 ◽

2010 ◽

Vol 39 (1) ◽

pp. 42-48 ◽

Cited By ~ 59

Author(s):

E. Georgakarakos ◽

C.V. Ioannou ◽

Y. Kamarianakis ◽

Y. Papaharilaou ◽

T. Kostas ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Wall Stress ◽

Geometric Parameters ◽

Aneurysm Wall ◽

Abdominal Aortic ◽

Abdominal Aortic Aneurysm Wall

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Role of vascular endothelial growth factor-A in development of abdominal aortic aneurysm

Cardiovascular Research ◽

10.1093/cvr/cvr080 ◽

2011 ◽

Vol 91 (2) ◽

pp. 358-367 ◽

Cited By ~ 48

Author(s):

Hidehiro Kaneko ◽

Toshihisa Anzai ◽

Toshiyuki Takahashi ◽

Takashi Kohno ◽

Masayuki Shimoda ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Abdominal Aortic Aneurysm ◽

Growth Factor ◽

Aortic Aneurysm ◽

Vascular Endothelial ◽

Abdominal Aortic ◽

Endothelial Growth Factor

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SM22α Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage-Derived circRasGEF1B

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/5564884 ◽

2021 ◽

Vol 2021 ◽

pp. 1-20

Author(s):

Pin Lv ◽

Ya-Juan Yin ◽

Peng Kong ◽

Li Cao ◽

Hao Xi ◽

...

Keyword(s):

Smooth Muscle ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Vascular Smooth Muscle ◽

Inflammatory Cell ◽

Activated Macrophages ◽

Abdominal Aortic ◽

Specific Manner ◽

Higher Sensitivity

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α-/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM ( P < 0.01 ), and apoptosis of Sm22α-/- VSMCs was higher than that of WT VSMCs ( P < 0.001 ). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α-/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α-/- VSMCs have a higher sensitivity to apoptosis.

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Abstract 15228: Role of Sympathetic Innervation in the Pathogenesis of Abdominal Aortic Aneurysm

Circulation ◽

10.1161/circ.142.suppl_3.15228 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Bin JIANG ◽

Yugang Liu ◽

Guillermo A Ameer

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Sympathetic Innervation ◽

Nerve Fibers ◽

Elastic Fibers ◽

Surgical Removal ◽

Infrarenal Aorta ◽

Abdominal Aortic ◽

Nerve Bundles

Introduction: The objective of this study is to understand the role of neurological factors, specifically those from the perivascular sympathetic nervous system (SNS), on the initiation and development of Abdominal Aortic Aneurysm (AAA). Hypothesis: We hypothesize that the formation of AAA is associated with the loss of perivascular SNS-induced vasoconstriction specific to the aneurysm region. Methods: We developed a rat Abdominal Aortic Denervation (AAD) model, where the infrarenal aorta of Spauge Dawley rats was denervated with surgical removal of nerve fibers and chemical denervation with 10% phenol ( Figure. A ). A sham control group was included where the infrarenal aorta was treated with PBS. The arteries were harvested at 1 month after the surgeries for histological assessment. Results: The denervated aortas exhibited significant thinning of the aortic wall including the media and the adventitia, compared to the sham controls ( Figure. B ). Moreover, degradation of elastin, demonstrated by the fragmentation of elastic fibers and the decreased number of lamellar units, was also observed in the dennervated aortas in comparison to the sham controls. While the control aortas were well innervated with perivascular nerve bundles adjacent to the adventitia, no nerves were found surrounding the denervated aortas, suggesting successful denervation. Conclusions: We generated an AAD model that could be used for mechanistic understanding and therapeutic development of AAA. The preliminary data suggest a direct link between the lack of aortic sympathetic innervation and AAA formation. Long-term studies are currently underway to further characterize changes in the aortic walls after sympathetic denervation. Figure. (A) Illustration of the denervated region on the rat infrarenal aorta. ( B ) Histological staining of control and denervated rat abdominal aortas at 1 month after surgery. Yellow stars: para-aortic nerve bundles. Scale bar = 200 μm.

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Abstract 667: The Role of Aortic Wall-Nuclear Factor- kappa B (NF-kB) Signaling in Formation of Dissecting Aortic Aneurysms

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.667 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Talha Ijaz ◽

Hong Sun ◽

Adrian Recinos ◽

Ronald G Tilton ◽

Allan R Brasier

Keyword(s):

Flow Cytometry ◽

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Aortic Wall ◽

Aortic Rupture ◽

Aortic Aneurysms ◽

Tunel Staining ◽

Abdominal Aortic ◽

Significant Difference

Introduction: Abdominal aortic aneurysm is a devastating disease since it can lead to aortic rupture and instantaneous death. We previously demonstrated that IL-6 secreted from the aortic wall is necessary for the development of abdominal aortic aneurysm and dissection (AAD). Since IL-6 is a NF-kB/RelA dependant gene, we investigated the role of aortic wall- NF-kB/RelA signaling in the development of AAD. Methods and Results: To test the role of aortic wall-RelA, we utilized Cre-Lox technology to delete RelA from aortic cells. Tamoxifen-inducible, Col1a2-promoter driven Cre mice (Col1a2-Cre) were crossed with mT/mG Cre-reporter mice to determine which aortic cells undergo genetic recombination after Cre activation. Flow cytometry analysis of the aortic wall indicated that 88% of the genetically recombined cells were SMCs and 8% were fibroblasts. Next, RelA floxed (RelA f/f) mice, generated in our lab, were crossed with Col1a2-Cre mice. RelA f/f Cre+ and RelA f/f Cre- were stimulated with tamoxifen for 10 days to generate aortic-RelA deficient (Ao-RelA-/-) or wild-type (Ao-RelA+/+) transgenics. Flow cytometry, qRT-PCR, and immunohistochemistry analysis suggested a depletion of aortic-RelA greater than 60%. To test the role of Ao-RelA in AAD, Ao-RelA -/- (n= 20) and Ao-RelA +/+ (n=14) mice were infused with angiotensin II for 7 days. Surprisingly, 20% of Ao-RelA-/- mice died from development of AAD and aortic rupture while no deaths were observed in Ao-RelA+/+ group. In addition, 40% of Ao-RelA-/- mice developed AAD compared to 14% of Ao-RelA+/+ mice. There was no significant difference in TUNEL staining or ERTR7+ fibroblast population between the two groups. Conclusion: Our studies suggest that aortic wall-RelA may be necessary for protection from AAD.

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Abstract 487: Systemic Administration of Target-Seeking, Vessel Penetrating Recombinant Decorin Fusion Protein, Car-DCN, Reduces Severity of Abdominal Aortic Aneurysm in Mice

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.37.suppl_1.487 ◽

2017 ◽

Vol 37 (suppl_1) ◽

Author(s):

Yue (Steve) Shen ◽

Valerio Russo ◽

Matthew Zeglinski ◽

Stephanie Sellers ◽

Zhengguo Wu ◽

...

Keyword(s):

Abdominal Aortic Aneurysm ◽

Aortic Aneurysm ◽

Fusion Protein ◽

Vessel Wall ◽

C Terminus ◽

Abdominal Aortic ◽

Homing Peptide ◽

Apoe Ko Mice ◽

Dependent Mechanism

Objective: Decorin (DCN) is a small leucine-rich proteoglycan that mediates collagen fibrollogenesis, organization, and tensile strength. DCN is reduced in abdominal aortic aneurysm (AAA) through a Granzyme B-dependent mechanism resulting in vessel wall instability and aneurysm formation. A recombinant decorin fusion protein CAR-DCN was engineered with an extended C-terminus comprised of CAR homing peptide that recognizes inflammatory blood vessels and penetrates deep into the vessel wall. In the present study, we sought to evaluate the role of systemically administered CAR-DCN in AAA progression and rupture rate in a murine model. Approach and Results: To induce aneurysm, apolipoprotein E knockout (ApoE-KO) mice were infused with 28 days of angiotensin II (AngII). CAR-DCN or vehicle was systemically administrated until day 15. We observed a significant increase in the survival of CAR-DCN-treated mice (93%) compared to vehicle controls (60%). Although the incidence of AAA onset was similar between vehicle and CAR-DCN groups, the severity of aneurysm in the CAR-DCN group was significantly reduced. Furthermore, histological analysis revealed that CAR-DCN treatment significantly increased DCN and collagen levels in aortic walls compares to vehicle controls. Conclusions: CAR-DCN administration attenuated the severity of Ang II-induced AAA in mice by reinforcing the vessel wall. CAR-DCN may represent a novel therapeutic strategy to attenuate AAA progression and rupture.

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