scholarly journals Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans

2018 ◽  
Vol 123 (6) ◽  
pp. 660-672 ◽  
Author(s):  
Yoshito Yamashiro ◽  
Bui Quoc Thang ◽  
Seung Jae Shin ◽  
Caroline Antunes Lino ◽  
Tomoyuki Nakamura ◽  
...  
Keyword(s):  
Elastic Fiber ◽  
Mechanical Stretch ◽  
Aortic Aneurysms ◽  
Matricellular Protein ◽  
Ang Ii ◽  
Thoracic Aortic Aneurysms ◽  
Aneurysm Formation ◽  
Thrombospondin 1 ◽  
Elastic Lamina

Rationale: Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated. Objective: The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy. Methods and Results: We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4 SMKO ; termed SMKO [SMC-specific knockout]), in which deletion of Fbln4 (fibulin-4) leads to disruption of the elastin-contractile units caused by a loss of elastic lamina-SMC connections. In this mouse, upregulation of Egr1 (early growth response 1) and angiotensin-converting enzyme leads to activation of Ang II (angiotensin II) signaling. Here, we showed that the matricellular protein, Thbs1 (thrombospondin-1), was highly upregulated in SMKO ascending aortas and in human thoracic aortic aneurysms. Thbs1 was induced by mechanical stretch and Ang II in SMCs, for which Egr1 was required, and reduction of Fbln4 sensitized the cells to these stimuli and led to higher expression of Egr1 and Thbs1. Deletion of Thbs1 in SMKO mice prevented the aneurysm formation in ≈80% of DKO (SMKO;Thbs1 knockout) animals and suppressed Ssh1 (slingshot-1) and cofilin dephosphorylation, leading to the formation of normal actin filaments. Furthermore, elastic lamina-SMC connections were restored in DKO aortas, and mechanical testing showed that structural and material properties of DKO aortas were markedly improved. Conclusions: Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.

CCN2 (Cellular Communication Network Factor 2) Deletion Alters Vascular Integrity and Function Predisposing to Aneurysm Formation

Hypertension ◽  
2021 ◽  
Author(s):  
R. Rodrigues-Díez Raul ◽  
Antonio Tejera-Muñoz ◽  
Vanesa Esteban ◽  
B. Steffensen Lasse ◽  
Raquel Rodrigues-Díez ◽  
...  
Keyword(s):  
Communication Network ◽  
Rapid Development ◽  
Cellular Communication ◽  
Aortic Aneurysms ◽  
Matricellular Protein ◽  
Ang Ii ◽  
Mineralocorticoid Receptor Antagonist ◽  
Functional Changes ◽  
Aneurysm Formation ◽  
Cellular Communication Network

Background: CCN2 (cellular communication network factor 2) is a matricellular protein involved in cell communication and microenvironmental signaling responses. CCN2 is known to be overexpressed in several cardiovascular diseases, but its role is not completely understood. Methods: Here, CCN2 involvement in aortic wall homeostasis and response to vascular injury was investigated in inducible Ccn2 -deficient mice, with induction of vascular damage by infusion of Ang II (angiotensin II; 15 days), which is known to upregulate CCN2 expression in the aorta. Results: Ang II infusion in CCN2-silenced mice lead to 60% mortality within 10 days due to rapid development and rupture of aortic aneurysms, as evidenced by magnetic resonance imaging, echography, and histological examination. Ccn2 deletion decreased systolic blood pressure and caused aortic structural and functional changes, including elastin layer disruption, smooth muscle cell alterations, augmented distensibility, and increased metalloproteinase activity, which were aggravated by Ang II administration. Gene ontology analysis of RNA sequencing data identified aldosterone biosynthesis as one of the most enriched terms in CCN2-deficient aortas. Consistently, treatment with the mineralocorticoid receptor antagonist spironolactone before and during Ang II infusion reduced aneurysm formation and mortality, underscoring the importance of the aldosterone pathway in Ang II–induced aorta pathology. Conclusions: CCN2 is critically involved in the functional and structural homeostasis of the aorta and in maintenance of its integrity under Ang II–induced stress, at least, in part, by disruption of the aldosterone pathway. Thus, this study opens new avenues to future studies in disorders associated to vascular pathologies.

Angiotensin II is associated with activation of NF-κB-mediated genes and downregulation of PPARs

2002 ◽  
Vol 11 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Doris M. Tham ◽  
Baby Martin-McNulty ◽  
Yi-xin Wang ◽  
Dennis W. Wilson ◽  
Ronald Vergona ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Adhesion Molecule ◽  
Vascular Inflammation ◽  
Aortic Aneurysms ◽  
Intercellular Adhesion Molecule ◽  
Ang Ii ◽  
Inflammatory Genes ◽  
Apoe Ko Mice ◽  
Apoe Ko

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-κB (NF-κB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-κB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-α and PPAR-γ mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-κB with increases in both p52 and p65 NF-κB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-κB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-α and -γ by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.

Abstract 598: Deletion of Microsomal PGE Synthase-1 Decreases Oxidative Stress and Protects Against Abdominal Aortic Aneurysm Formation in Angiotensin II-Infused Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Miao Wang ◽  
Jane Stubbe ◽  
Eric Lee ◽  
Wenliang Song ◽  
Emanuela Ricciotti ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Aortic Aneurysms ◽  
Ang Ii ◽  
Abdominal Aortic ◽  
Density Lipoprotein Receptor ◽  
The Impact

Microsomal (m) prostaglandin (PG) E 2 synthase(S)-1, an enzyme that catalyzes the isomerization of the cyclooxygenase (COX) product, PGH 2 , into PGE 2 , is a major source of PGE 2 in vivo . mPGES-1 deletion in mice was found to modulate experimentally evoked pain and inflammation and atherogenesis is retarded in mPGES-1 knockout (KO) mice. The impact of mPGES-1 deletion on formation of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) was studied in mice lacking the low density lipoprotein receptor (LDLR −/− ). AngII infusion increased aortic macrophage recruitment and nitrotyrosine staining while upregulating both mPGES-1 and COX-2 and urinary excretion of the major metabolite of PGE 2 (PGE-M). Deletion of mPGES-1 decreased both the incidence and severity of AAA and depressed excretion of both PGE-M and 8, 12-iso-iPF 2a -VI, which reflects lipid peroxidation in vivo . While Ang II infusion augmented prostaglandin biosynthesis, deletion of mPGES-1 resulted in rediversion to PGD 2 , reflected by its major urinary metabolite. However, deletion of the PGD 2 receptor, DP1, did not affect AAA in Ang II infused LDLR −/− mice. These observations indicate that deletion of mPGES-1 protects against AAA formation by AngII in hyperlipidemic mice, perhaps by decreasing oxidative stress. Inhibition of mPGES-1 may represent an effective treatment to limit aneurysm occurrence and expansion.

scholarly journals miR‐133a Replacement Attenuates Thoracic Aortic Aneurysm in Mice

2021 ◽  
Author(s):  
Adam W. Akerman ◽  
Elizabeth N. Collins ◽  
Andrew R. Peterson ◽  
Lauren B. Collins ◽  
Jessica K. Harrison ◽  
...  
Keyword(s):  
Murine Model ◽  
Linear Regression Analysis ◽  
Inverse Correlation ◽  
Aortic Aneurysms ◽  
Luciferase Reporter ◽  
Proteolytic Activation ◽  
Thoracic Aortic Aneurysms ◽  
Over Expression ◽  
Cellular Phenotypes

Background Thoracic aortic aneurysms (TAAs) occur because of abnormal remodeling of aortic extracellular matrix and are accompanied by the emergence of proteolytically active myofibroblasts. The microRNA miR‐133a regulates cellular phenotypes and is reduced in clinical TAA specimens. This study tested the hypothesis that miR‐133a modulates aortic fibroblast phenotype, and overexpression by lentivirus attenuates the development of TAA in a murine model. Methods and Results TAA was induced in mice. Copy number of miR‐133a was reduced in TAA tissue and linear regression analysis confirmed an inverse correlation between aortic diameter and miR‐133a. Analyses of phenotypic markers revealed an mRNA expression profile consistent with myofibroblasts in TAA tissue. Fibroblasts were isolated from the thoracic aortae of mice with/without TAA. When compared with controls, miR‐133a was reduced, migration was increased, adhesion was reduced, and the ability to contract a collagen disk was increased. Overexpression/knockdown of miR‐133a controlled these phenotypes. After TAA induction in mice, a single tail‐vein injection of either miR‐133a overexpression or scrambled sequence (control) lentivirus was performed. Overexpression of miR‐133a attenuated TAA development. The pro‐protein convertase furin was confirmed to be a target of miR‐133a by luciferase reporter assay. Furin was elevated in this murine model of TAA and repressed by miR‐133a replacement in vivo resulting in reduced proteolytic activation. Conclusions miR‐133a regulates aortic fibroblast phenotype and over‐expression prevented the development of TAA in a murine model. These findings suggest that stable alterations in aortic fibroblasts are associated with development of TAA and regulation by miR‐133a may lead to a novel therapeutic strategy.

Abstract 18182: Phosphodiesterase 10A Regulates Vascular Inflammation and Pathogenesis of Abdominal Aortic Aneurysms

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Yujun Cai ◽  
Yujun Cai ◽  
Chen Yan ◽  
Raul J Guzman
Keyword(s):  
Vascular Inflammation ◽  
Critical Role ◽  
Abdominal Aortic Aneurysms ◽  
Peritoneal Macrophages ◽  
Aortic Aneurysms ◽  
Causative Role ◽  
Ang Ii ◽  
Monocyte Chemoattractant Protein 1 ◽  
Abdominal Aortic

Rationale: Abdominal aortic aneurysms (AAA) are characterized by aortic enlargement and underlying weakness of the vessel wall. Experimental and clinical evidence suggests that vascular inflammation is a central trigger of AAA formation. Phosphodiesterases (PDEs), known regulators of cyclic nucleotide signaling, play a critical role in vascular inflammation. Objective: In this study, we sought to determine the role and function of PDE10A in vascular inflammation and AAA formation. Methods and Results: Extensive evidence suggests that angiotensin II (Ang II) signaling plays an important causative role in AAA formation. Therefore, Real-time PCR array for all 22 known PDE genes was performed in control and Ang II-treated VSMCs. We observed that PDE10A elicited the highest levels of induction by Ang II among all PDEs. Moreover, we found that PDE10A was dramatically upreguated in the Ang II-infused AAA mouse model and in human AAA specimens. PDE10A was primarily expressed in medial VSMCs and infiltrating macrophages in AAA. More importantly, deficiency of PDE10A or PDE10A inhibition significantly attenuated AAA formation in vivo. In cultured VSMCs, knockdown of PDE10A with specific siRNA and inhibition of PDE10A by papaverine markedly suppressed Ang II-induced vascular cell adhesion molecule 1 (VCAM-1), monocyte chemoattractant protein-1 (MCP-1) and MMP2 expression. Deficiency of PDE10A also blocked lipopolysaccharide (LPS)-induced TNF-α, MCP-1, and MMP9 expression in peritoneal macrophages isolated from PDE10A knockout mice. Further mechanistic studies revealed that histone deacetylase 5 (HDAC5) plays an important role in PDE10A-regulated vascular inflammation via cAMP-dependent protein kinase (PKA). Conclusions: These findings demonstrate that PDE10A is an important regulator of vascular inflammation and AAA development. They further provide evidence for PDE10A as a potential therapeutic target for aortic aneurysms and other vascular diseases.

Abstract 149: Regulator of G-Protein Signaling-1 Modulates Leukocyte Trafficking in Atherosclerosis and Aortic Aneurysm Formation Through Chemokine Receptor Desensitization

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jyoti Patel ◽  
Eileen McNeill ◽  
Gillian Douglas ◽  
Ashley Hale ◽  
Joseph de Bono ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aortic Aneurysm ◽  
G Protein ◽  
Aneurysm Rupture ◽  
Aortic Aneurysms ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Aneurysm Formation ◽  
Inflammatory Monocytes

The regulation of macrophage recruitment and retention into the vascular wall is critical in the progression of atherosclerosis and aortic aneurysm formation. This can be mediated by chemokine activation of multiple G-protein coupled receptors. The Regulator of G-Protein Signaling-1 (RGS1) acts to deactivate the intracellular response to sustained chemokine stimulation. We have found that RGS1 is upregulated with atherosclerotic plaque progression and with monocyte-macrophage activation but its role is unknown. Rgs1-/- macrophages have significantly enhanced migratory responses to atherogenic chemokines and have impaired desensitization to chemokine re-stimulation (p<0.001). In vivo, RGS1 has a role in the accumulation of macrophages in atherosclerotic lesions and during Angiotensin II (AngII) aortic aneurysm rupture. In the absence of RGS1, atherosclerosis and macrophage accumulation is attenuated in early lesions in the aortic root and aortas of ApoE-/- mice (p<0.001). Rgs1-/- mice are protected from AngII induced aneurysm rupture compared to ApoE-/- mice with 94% survival vs. 56%. Rgs1-/- mice have significantly fewer CD11b+ myeloid cells and CD14+ macrophages in aortas than ApoE-/- mice (p<0.05) after 5 days of AngII infusion. Following bone marrow transplantation, recipient mice receiving ApoE-/- bone marrow were more susceptible to aortic aneurysm rupture (p=0.0124), indicating bone marrow-derived RGS1 is required for aneurysm rupture. Furthermore, AngII treatment increased systolic blood pressure to a greater extent in Rgs1-/- mice than ApoE-/- mice suggesting aneurysm formation in these mice is independent of AngII induced hypertension and this is mediated by vascular-derived RGS1. To gain insight into the mechanism by which RGS1 regulates trafficking, we selectively labelled inflammatory monocytes in vivo to track their movement into aortas following AngII infusion. We found an accumulation of labelled CD45+ cells in the aortas of ApoE-/- mice from day 3 to day 5 but not in Rgs1-/- mice indicating RGS1 as a regulator of macrophage retention in aortic aneurysms. These findings identify a novel role for RGS1 in leukocyte retention in vascular inflammation, highlighting RGS1 as a potential target in cardiovascular disease.

scholarly journals Loss of FoxO3a prevents aortic aneurysm formation through maintenance of VSMC homeostasis

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Weiling Lu ◽  
Yu Zhou ◽  
Shan Zeng ◽  
Lintao Zhong ◽  
Shiju Zhou ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Smooth Muscle Actin ◽  
Critical Role ◽  
Inhibitory Effect ◽  
Aortic Aneurysms ◽  
Phenotypic Switching ◽  
Ang Ii

AbstractVascular smooth muscle cell (VSMC) phenotypic switching plays a critical role in the formation of abdominal aortic aneurysms (AAAs). FoxO3a is a key suppressor of VSMC homeostasis. We found that in human and animal AAA tissues, FoxO3a was upregulated, SM22α and α-smooth muscle actin (α-SMA) proteins were downregulated and synthetic phenotypic markers were upregulated, indicating that VSMC phenotypic switching occurred in these diseased tissues. In addition, in cultured VSMCs, significant enhancement of FoxO3a expression was found during angiotensin II (Ang II)-induced VSMC phenotypic switching. In vivo, FoxO3a overexpression in C57BL/6J mice treated with Ang II increased the formation of AAAs, whereas FoxO3a knockdown exerted an inhibitory effect on AAA formation in ApoE−/− mice infused with Ang II. Mechanistically, FoxO3a overexpression significantly inhibited the expression of differentiated smooth muscle cell (SMC) markers, activated autophagy, the essential repressor of VSMC homeostasis, and promoted AAA formation. Our study revealed that FoxO3a promotes VSMC phenotypic switching to accelerate AAA formation through the P62/LC3BII autophagy signaling pathway and that therapeutic approaches that decrease FoxO3a expression may prevent AAA formation.

scholarly journals P.08 Biomechanical Characterization of Ascending Thoracic Aortic Aneurysms in Humans: A Continuum Approach to in vivo Deformations

2020 ◽  
Vol 26 (Supplement 1) ◽  
pp. S28
Author(s):  
Shaiv Parikh ◽  
Bart Spronck ◽  
Gijs Debeij ◽  
Berta Ganizada ◽  
Mitch Ramaekers ◽  
...  
Keyword(s):  
Aortic Aneurysms ◽  
Continuum Approach ◽  
Thoracic Aortic Aneurysms

scholarly journals β-Arrestin-biased AT1R stimulation promotes cell survival during acute cardiac injury

2012 ◽  
Vol 303 (8) ◽  
pp. H1001-H1010 ◽  
Author(s):  
Ki-Seok Kim ◽  
Dennis Abraham ◽  
Barbara Williams ◽  
Jonathan D. Violin ◽  
Lan Mao ◽  
...  
Keyword(s):  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Cardiac Contractility ◽  
Cardiac Injury ◽  
Mechanical Stretch ◽  
Ang Ii ◽  
Biased Signaling ◽  
Pharmacological Blockade

Pharmacological blockade of the ANG II type 1 receptor (AT1R) is a common therapy for treatment of congestive heart failure and hypertension. Increasing evidence suggests that selective engagement of β-arrestin-mediated AT1R signaling, referred to as biased signaling, promotes cardioprotective signaling. Here, we tested the hypothesis that a β-arrestin-biased AT1R ligand TRV120023 would confer cardioprotection in response to acute cardiac injury compared with the traditional AT1R blocker (ARB), losartan. TRV120023 promotes cardiac contractility, assessed by pressure-volume loop analyses, while blocking the effects of endogenous ANG II. Compared with losartan, TRV120023 significantly activates MAPK and Akt signaling pathways. These hemodynamic and biochemical effects were lost in β-arrestin-2 knockout (KO) mice. In response to cardiac injury induced by ischemia reperfusion injury or mechanical stretch, pretreatment with TRV120023 significantly diminishes cell death compared with losartan, which did not appear to be cardioprotective. This cytoprotective effect was lost in β-arrestin-2 KO mice. The β-arrestin-biased AT1R ligand, TRV120023, has cardioprotective and functional properties in vivo, which are distinct from losartan. Our data suggest that this novel class of drugs may provide an advantage over conventional ARBs by supporting cardiac function and reducing cellular injury during acute cardiac injury.

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