Endothelium as a Potential Target for Treatment of Abdominal Aortic Aneurysm

Sun, Jun; Deng, Hongping; Zhou, Zhen; Xiong, Xiaoxing; Gao, Ling

doi:10.1155/2018/6306542

Cited by 51 publications

(55 citation statements)

References 105 publications

(115 reference statements)

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“…Previous ex vivo studies demonstrated more marked vascular permeability in patients with AAAs and found an association with a higher rupture risk 4,5 .…”

Section: Discussionmentioning

confidence: 95%

Noninvasive imaging of vascular permeability to predict the risk of rupture in abdominal aortic aneurysms using an albumin-binding probe

Adams

Brangsch

Reimann

et al. 2020

Sci Rep

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Abdominal aortic aneurysm (AAA) remains a fatal disease. its development encompasses a complex interplay between hemodynamic stimuli on and changes in the arterial wall. currently available biomarkers fail to predict the risk of AAA rupture independent of aneurysm size. therefore, novel biomarkers for AAA characterization are needed. in this study, we used a mouse model of AAA to investigate the potential of magnetic resonance imaging (MRi) with an albumin-binding probe to assess changes in vascular permeability at different stages of aneurysm growth. Two imaging studies were performed: a longitudinal study with follow-up and death as endpoint to predict rupture risk and a week-by-week study to characterize AAA development. AAAs, which eventually ruptured, demonstrated a significantly higher in vivo MR signal enhancement from the albumin-binding probe (p = 0.047) and a smaller nonenhancing thrombus area compared to intact AAAs (p = 0.001). The ratio of albumin-binding-probe enhancement of the aneurysm wall to size of nonenhancing-thrombus-area predicted AAA rupture with high sensitivity/specificity (100%/86%). More advanced aneurysms with higher vascular permeability demonstrated an increased uptake of the albumin-binding-probe. these results indicate that MRi with an albumin-binding probe may enable noninvasive assessment of vascular permeability in murine AAAs and prediction of rupture risk. Abdominal aortic aneurysm (AAA) poses an increasing burden on healthcare systems and is among the challenges currently facing society, with prevalence ranging from 5% to 10% in Western populations 1. AAA development is a multifactorial, mainly degenerative process encompassing a complex interplay between hemodynamic stimuli on and changes in the arterial wall, including endothelial dysfunction 2-7. Rupture of AAA is a life-threatening complication and surgical emergency with high mortality 1. While larger (≥55 mm), symptomatic, or fast-growing (>10 mm/year) AAAs are recommended to undergo endovascular or operative repair as the only available treatment options, patients with smaller AAAs, who are considered to have a lower risk of rupture, are often monitored with non-invasive imaging 8. By contrast, the management of medium-sized AAAs remains controversial 9. Apart from diameter and growth rate, there is currently no recognized biomarker for evaluating AAA characteristics and rupture risk 1. The main limitation of aneurysm diameter as the primary criterion for intervention is that it fails to account for smaller aneurysms with high rupture risk and also for large

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“…Previous ex vivo studies demonstrated more marked vascular permeability in patients with AAAs and found an association with a higher rupture risk 4,5 .…”

Section: Discussionmentioning

confidence: 95%

Noninvasive imaging of vascular permeability to predict the risk of rupture in abdominal aortic aneurysms using an albumin-binding probe

Adams

Brangsch

Reimann

et al. 2020

Sci Rep

View full text Add to dashboard Cite

show abstract

“…In particular, aneurysms have been described as a weakening of the aortic wall due to SMC-specific defects, resulting in the dissection of the vessel ( Takeda et al, 2018 ). Only recently have a few studies started considering the endothelium as a potential therapeutic target in aortic pathologies ( van de Pol et al, 2017 ; Sun et al, 2018 ). The close proximity of ECs with SMCs makes their cross-talk essential for aortic development and homeostasis ( Lilly, 2014 ; Stratman et al, 2017 ; Segers et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Endothelial TGF-β signaling instructs smooth muscle cell development in the cardiac outflow tract

Boezio

Bensimon-Brito

Piesker

et al. 2020

eLife

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The development of the cardiac outflow tract (OFT), which connects the heart to the great arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) cells. Defects in OFT development can lead to severe malformations, including aortic aneurysms, which are frequently associated with impaired TGF-β signaling. To better understand the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT: alk5-/- OFTs exhibit increased EC numbers as well as extracellular matrix (ECM) and SMC disorganization. Surprisingly, endothelial-specific alk5 overexpression in alk5-/- rescues the EC, ECM, and SMC defects. Transcriptomic analyses reveal downregulation of the ECM gene fibulin-5, which when overexpressed in ECs ameliorates OFT morphology and function. These findings reveal a new requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important role for the endothelium in the etiology of aortic malformations.

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“…In particular, aneurysms have been described as a weakening of the aortic wall due to SMC-specific defects, resulting in the dissection of the vessel (Takeda et al, 2018). Only recently have a few studies started considering the endothelium as a potential therapeutic target in OFT and aortic pathologies (van de Pol et al, 2017; Sun et al, 2018). The close proximity of ECs with SMCs makes their cross-talk essential for aortic development and homeostasis (Lilly, 2014; Stratman et al, 2017; Segers et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

Boezio

Bensimon-Brito

Piesker

et al. 2020

Preprint

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19The development of the cardiac outflow tract (OFT), which connects the heart to the great 20 arteries, relies on a complex crosstalk between endothelial (ECs) and smooth muscle (SMCs) 21 cells. Defects in OFT development can lead to severe malformations, including aortic 22 aneurysms, which have often been associated with impaired TGF-β signaling. To further 23 investigate the role of TGF-β signaling in OFT formation, we generated zebrafish lacking the 24 type I TGF-β receptor Alk5 and found a strikingly specific dilation of the OFT. alk5 mutants 25 also exhibit increased EC numbers, extracellular matrix (ECM) and SMC disorganization. 26 Surprisingly, endothelial-specific alk5 overexpression in alk5 mutants rescues both 27 endothelial and SMC defects. Furthermore, modulation of the ECM gene fibulin-5, a TGF-β 28 target, partially restores OFT morphology and function. These findings reveal a new 29 requirement for endothelial TGF-β signaling in OFT morphogenesis and suggest an important 30 role for the endothelium in the etiology of aortic malformations.31 32

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Endothelium as a Potential Target for Treatment of Abdominal Aortic Aneurysm

Cited by 51 publications

References 105 publications

Noninvasive imaging of vascular permeability to predict the risk of rupture in abdominal aortic aneurysms using an albumin-binding probe

Noninvasive imaging of vascular permeability to predict the risk of rupture in abdominal aortic aneurysms using an albumin-binding probe

Endothelial TGF-β signaling instructs smooth muscle cell development in the cardiac outflow tract

Endothelial TGF-β signaling instructs smooth muscle development in the cardiac outflow tract

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