scholarly journals High serum thrombospondin-1 concentration is associated with slower abdominal aortic aneurysm growth and deficiency of thrombospondin-1 promotes angiotensin II induced aortic aneurysm in mice

2017 ◽  
Vol 131 (12) ◽  
pp. 1261-1281 ◽  
Author(s):  
Smriti Murali Krishna ◽  
Sai Wang Seto ◽  
Roby Jose ◽  
Jiaze Li ◽  
Joseph Moxon ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Ex Vivo ◽  
High Serum ◽  
Matricellular Protein ◽  
Body Tissues ◽  
Age Related ◽  
Abdominal Aortic ◽  
Thrombospondin 1

Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Thrombospondin-1 (TSP-1; gene Thbs1) is a member of the matricellular protein family important in the control of extracellular matrix (ECM) remodelling. In the present study, the association of serum TSP-1 concentration with AAA progression was assessed in 276 men that underwent repeated ultrasound for a median 5.5 years. AAA growth was negatively correlated with serum TSP-1 concentration (Spearman’s rho −0.129, P=0.033). Men with TSP-1 in the highest quartile had a reduced likelihood of AAA growth greater than median during follow-up (OR: 0.40; 95% confidence interval (CI): 0.19–0.84, P=0.016, adjusted for other risk factors). Immunohistochemical staining for TSP-1 was reduced in AAA body tissues compared with the relatively normal AAA neck. To further assess the role of TSP-1 in AAA initiation and progression, combined TSP-1 and apolipoprotein deficient (Thbs1−/−ApoE−/−, n=20) and control mice (ApoE−/−, n=20) were infused subcutaneously with angiotensin II (AngII) for 28 days. Following AngII infusion, Thbs1−/− ApoE−/− mice had larger AAAs by ultrasound (P=0.024) and ex vivo morphometry measurement (P=0.006). The Thbs1−/−ApoE−/− mice also showed increased elastin filament degradation along with elevated systemic levels and aortic expression of matrix metalloproteinase (MMP)-9. Suprarenal aortic segments and vascular smooth muscle cells (VSMCs) isolated from Thbs1−/−ApoE−/− mice showed reduced collagen 3A1 gene expression. Furthermore, Thbs1−/−ApoE−/− mice had reduced aortic expression of low-density lipoprotein (LDL) receptor-related protein 1. Collectively, findings from the present study suggest that TSP-1 deficiency promotes maladaptive remodelling of the ECM leading to accelerated AAA progression.

scholarly journals Myeloid-Derived TSP1 (Thrombospondin-1) Contributes to Abdominal Aortic Aneurysm Through Suppressing Tissue Inhibitor of Metalloproteinases-1

2020 ◽  
Vol 40 (12) ◽  
Author(s):  
Huan Yang ◽  
Ting Zhou ◽  
Christine M. Sorenson ◽  
Nader Sheibani ◽  
Bo Liu
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Molecular Mechanisms ◽  
Inflammatory Cells ◽  
Matricellular Protein ◽  
Tissue Inhibitor Of Metalloproteinases ◽  
Tissue Inhibitor ◽  
Abdominal Aortic ◽  
Thrombospondin 1 ◽  
Inflammatory Macrophages

Objective: Abdominal aortic aneurysm is characterized by the progressive loss of aortic integrity and accumulation of inflammatory cells primarily macrophages. We previously reported that global deletion of matricellular protein TSP1 (thrombospondin-1) protects mice from aneurysm formation. The objective of the current study is to investigate the cellular and molecular mechanisms underlying TSP1’s action in aneurysm. Approach and Results: Using RNA fluorescent in situ hybridization, we identified macrophages being the major source of TSP1 in human and mouse aneurysmal tissues, accounting for over 70% of cells that actively expressed Thbs1 mRNA. Lack of TSP1 in macrophages decreased solution-based gelatinase activities by elevating TIMP1 (tissue inhibitor of metalloproteinases-1) without affecting the major MMPs (matrix metalloproteinases). Knocking down Timp1 restored the ability of Thbs1 − /− macrophages to invade matrix. Finally, we generated Thbs1 flox/flox mice and crossed them with Lyz2-cre mice. In the CaCl 2 -induced model of abdominal aortic aneurysm, lacking TSP1 in myeloid cells was sufficient to protect mice from aneurysm by reducing macrophage accumulation and preserving aortic integrity. Conclusions: TSP1 contributes to aneurysm pathogenesis, at least in part, by suppressing TIMP1 expression, which subsequently enables inflammatory macrophages to infiltrate vascular tissues.

scholarly journals MFAP4 Deficiency Attenuates Angiotensin II-Induced Abdominal Aortic Aneurysm Formation Through Regulation of Macrophage Infiltration and Activity

2021 ◽  
Vol 8 ◽  
Author(s):  
Bartosz Pilecki ◽  
Paulo V. S. D. de Carvalho ◽  
Katrine L. Kirketerp-Møller ◽  
Anders Schlosser ◽  
Karin Kejling ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Apolipoprotein E ◽  
Macrophage Infiltration ◽  
Elastic Membrane ◽  
Ang Ii ◽  
Monocyte Migration ◽  
Age Related ◽  
Abdominal Aortic

Objective: Abdominal aortic aneurysm (AAA) is a common age-related vascular disease characterized by progressive weakening and dilatation of the aortic wall. Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix (ECM) protein involved in the induction of vascular remodeling. This study aimed to investigate if MFAP4 facilitates the development of AAA and characterize the underlying MFAP4-mediated mechanisms.Approach and Results: Double apolipoprotein E- and Mfap4-deficient (ApoE−/−Mfap4−/−) and control apolipoprotein E-deficient (ApoE−/−) mice were infused subcutaneously with angiotensin II (Ang II) for 28 days. Mfap4 expression was localized within the adventitial and medial layers and was upregulated after Ang II treatment. While Ang II-induced blood pressure increase was independent of Mfap4 genotype, ApoE−/−Mfap4−/− mice exhibited significantly lower AAA incidence and reduced maximal aortic diameter compared to ApoE−/− littermates. The ApoE−/−Mfap4−/− AAAs were further characterized by reduced macrophage infiltration, matrix metalloproteinase (MMP)-2 and MMP-9 activity, proliferative activity, collagen content, and elastic membrane disruption. MFAP4 deficiency also attenuated activation of integrin- and TGF-β-related signaling within the adventitial layer of AAA tissues. Finally, MFAP4 stimulation promoted human monocyte migration and significantly upregulated MMP-9 activity in macrophage-like THP-1 cells.Conclusion: This study demonstrates that MFAP4 induces macrophage-rich inflammation, MMP activity, and maladaptive remodeling of the ECM within the vessel wall, leading to an acceleration of AAA development and progression. Collectively, our findings suggest that MFAP4 is an essential aggravator of AAA pathology that acts through regulation of monocyte influx and MMP production.

Abstract 297: Segmental Aortic Stiffening is a Mechanism Driving Early Abdominal Aortic Aneurysm Pathogenesis

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Uwe Raaz ◽  
Alexander M Zöllner ◽  
Ryuji Toh ◽  
Futoshi Nakagami ◽  
Isabel N Schellinger ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aortic Wall ◽  
Ex Vivo ◽  
Wall Stress ◽  
Finite Elements Analysis ◽  
External Application ◽  
Abdominal Aortic ◽  
Aneurysm Growth ◽  
Aortic Stiffening

Stiffening of the aortic wall is a phenomenon consistently observed in abdominal aortic aneurysm (AAA). However, its role in AAA pathophysiology is largely undefined. Using an established murine elastase-induced AAA model, we demonstrate that segmental aortic stiffening (SAS) precedes aneurysm growth. Finite elements analysis (FEA)-based wall stress calculations reveal that early stiffening of the aneurysm-prone aortic segment leads to axial (longitudinal) stress generated by cyclic (systolic) tethering of adjacent, more compliant wall segments. Interventional stiffening of AAA-adjacent segments (via external application of surgical adhesive) significantly reduces aneurysm growth. These changes correlate with reduced segmental stiffness of the AAA-prone aorta (due to equalized stiffness in adjacent aortic segments), reduced axial wall stress, decreased production of reactive oxygen species (ROS), attenuated elastin breakdown, and decreased expression of inflammatory cytokines and macrophage infiltration, as well as attenuated apoptosis within the aortic wall. Cyclic pressurization of stiffened aortic segments ex vivo increases the expression of genes related to inflammation and extracellular matrix (ECM) remodeling. Finally, human ultrasound studies reveal that aging, a significant AAA risk factor, is accompanied by segmental infrarenal aortic stiffening. The present study introduces the novel concept of segmental aortic stiffening (SAS) as an early pathomechanism generating aortic wall stress and thereby triggering AAA growth. Therefore monitoring SAS by ultrasound might help to better identify patients at risk for AAA disease and better predict the susceptibility of small AAA to further growth. Moreover our results suggest that interventional mechanical stiffening of the AAA-adjacent aorta may be further tested as a novel treatment option to limit early AAA growth.

scholarly journals Matricellular protein CCN3 mitigates abdominal aortic aneurysm

2016 ◽  
Vol 126 (4) ◽  
pp. 1282-1299 ◽  
Author(s):  
Chao Zhang ◽  
Dustin van der Voort ◽  
Hong Shi ◽  
Rongli Zhang ◽  
Yulan Qing ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Matricellular Protein ◽  
Abdominal Aortic

scholarly journals Ex vivo repair of renal artery aneurysm associated with surgical treatment of abdominal aortic aneurysm

2004 ◽  
Vol 132 (7-8) ◽  
pp. 250-253
Author(s):  
Dusan Kostic ◽  
Lazar Davidovic ◽  
Drago Milutinovic ◽  
Radomir Sindjelic ◽  
Marko Dragas ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Renal Artery ◽  
Ex Vivo ◽  
Artery Aneurysm ◽  
Ptfe Graft ◽  
Dacron Graft ◽  
Renal Artery Aneurysm ◽  
Abdominal Aortic ◽  
The Right

INTRODUCTION Renal artery aneurysms is relatively uncommon with reported incidence ranges from 0.3% to 1%. However, considering all visceral artery aneurysms the percentage of renal artery aneurysms is relatively high between 15-25%. The distal forms of renal artery aneurysms sometimes require "ex vivo" reconstruction and kidney autotransplantation. CASE REPORT A 75-year-old male presented with the right abdominal and back pain. He suffered from a long history of arterial hypertension and chronic renal failure over the last few months (urea blood = 19.8 mmol/l; creatinine = 198 mmol/l). Duplex ultrasonography showed abdominal aortic aneurysm. Subsequent translumbarangiography revealed juxtarenal abdominal aortic aneurysm associated with distal right renal artery aneurysm. The operation was performed under combined thoracic epidural analgesia and general anesthesia using transperitoneal approach. After the laparotomy, the ascending colon was mobilized and reflected medially followed by Kocher maneuver. The result was visualization of the anterior aspect of the right kidney, the collecting system, ureter as well as the right renal vein and artery with large saccular aneurysm located distally. After mobilization of the renal vessels and careful dissection of the ureter, the kidney was explanted. The operation was continued by two surgical teams. The first team performed abdominal aortic aneurysm resection and reconstruction with bifurcated Dacron graft. The second team performed ex vivo reparation of renal artery aneurysm. All time during the explantation, the kidney was perfused by Collins' solution. The saccular right renal artery aneurysm 4 cm in diameter was located at the kidney hilus at the first bifurcation. Three branches originated from the aneurysm. The aneurysm was resected completely. The longest and widest of three branches arising from the aneurysmal sac was end-to-end anastomized with 6 mm PTFE graft. After this intervention, one of shorter arteries was implanted into the long artery, and another one into PTFE graft. After 30 minutes of explanation, autotransplantation of the kidney into the right iliac fossa was performed. The right renal vein was implanted into the inferior vein cava, and PTFE graft into the right limb of Dacron graft. Immediately following the completion of both anastomoses, large volume of urine was evident. Finally, ureteneocystostomy was performed with previous insertion of double "J" catheter. In the immediate postoperative period, renal function was restored to normal, while postoperative angiography revealed all patent grafts. DISCUSSION The most common causes of renal artery aneurysms are arteriosclerosis, as in our case, and fibro-muscular dysplasia. Very often, renal artery aneurysms are asymptomatic and discovered only during angiography in patients with aneurysmal and occlusive aortic disease. Other cases include: arterial hypertension, groin pain and acute or chronic renal failure. Due to relatively small number of evaluated cases, the risk of aneurysmal rupture is not known. According to some authors, the overall rupture rate of renal artery aneurysm is 5%, however, the rupture risk becomes higher in young pregnant woman. Several standard surgical procedures are available for the repair of renal artery aneurysms. These include saphenous vein angioplasty, bypass grafting, as well as ex vivo reconstruction with reimplantation or autotransplantation. Furthermore, interventional embolization therapy, as well as endovascular treatment with ePTFE covered stent, or autologous vein-coverage stent graft, have been also reported to be successful. CONCLUSION The major indications for surgical treatment of renal artery aneurysms are to eliminate the source of thromboembolism which leads to fixed renal hypertension and kidney failure, as well as prevention of aneurysmal rupture.

scholarly journals Endothelial Cell Tetrahydrobiopterin Modulates Sensitivity to Ang (Angiotensin) II–Induced Vascular Remodeling, Blood Pressure, and Abdominal Aortic Aneurysm

Hypertension ◽  
2018 ◽  
Vol 72 (1) ◽  
pp. 128-138 ◽  
Author(s):  
Surawee Chuaiphichai ◽  
Victoria S. Rashbrook ◽  
Ashley B. Hale ◽  
Lucy Trelfa ◽  
Jyoti Patel ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Abdominal Aortic Aneurysm ◽  
Endothelial Cell ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Remodeling ◽  
Abdominal Aortic

Abstract 279: Role of Caveolin-1 in Abdominal Aortic Aneurysm induced by Angiotensin II

2013 ◽  
Vol 33 (suppl_1) ◽  
Author(s):  
Takehiko Takayanagi ◽  
Kevin Crawford ◽  
Tomonori Kobayashi ◽  
Victor Rizzo ◽  
Satoru Eguchi
Keyword(s):  
Oxidative Stress ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Egf Receptor ◽  
Critical Role ◽  
Membrane Microdomains ◽  
Structural Protein ◽  
Caveolin 1 ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests that activation of the AT1 receptor by angiotensin II (AngII) in AAA formation. While several downstream signals and target proteins have been identified in this pathway, there is a huge void in our knowledge regarding the AngII-sensitive proximal events primarily responsible for AAA formation. We recently reported that caveolae membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation which linked to vascular remodeling induced by AngII. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that caveolin-1 (Cav1), a major structural protein of caveolae, in the vasculature plays a critical role for development of AAA via its regulation on ADAM17. 8 week old male Cav1-/- mice and the control C57Bl/6 wild-type (WT) mice were co-infused with AngII and BAPN, a lysyl oxidase inhibitor, to induce AAA. We found that Cav1-/- mice did not develop AAA compared to C57Bl/6 mice in spite of hypertension assessed by telemetry in both groups. This finding suggests that the AngII signaling essential for vascular contraction remains in place in Cav1-/- mice. We found an increased expression of ADAM17 and auto-phosphorylation of EGFR in WT abdominal aortae with aneurysms that were markedly attenuated in Cav1-/- mice infused with AngII+BAPN. Furthermore, Cav1-/- mice with the infusion showed less oxidative stress and ER stress than their WT counterparts as assessed by nitrotyrosine staining and KDEL/p-eIF2a staining, respectively. In conclusion, Cav1 and presumably vascular caveolae micro-domain appear to play a critical role in the formation of AAA in mice via regulation of the ADAM17/EGFR signaling axis and subsequent induction of ER/oxidative stress.

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