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.

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.

scholarly journals Extracellular Oncosomes Rich in Moonlighting Metalloproteinase (MMP3) Are Transmissive, Pro-Tumorigenic, and Induces Cellular Communication Network Factor 2 (CCN2/CTGF): CRISPR against Cancer

2020 ◽  
Author(s):  
Yuka Okusha ◽  
Takanori Eguchi ◽  
Manh Tien Tran ◽  
Chiharu Sogawa ◽  
Kaya Yoshida ◽  
...  
Keyword(s):  
Communication Network ◽  
Culture Media ◽  
Recipient Cell ◽  
Tissue Growth ◽  
Cellular Communication ◽  
Migration And Invasion ◽  
Metastatic Colon Cancer ◽  
Cell Nuclei ◽  
Cellular Communication Network

Matrix metalloproteinase 3 (MMP3) plays multiple roles in pro-tumorigenic proteolysis and in intracellular transcription. These include inducing connective tissue growth factor [CTGF, also known as cellular communication network factor 2 (CCN2)] and prompting a new definition of MMP3 as a moonlighting metalloproteinase. Members of the MMP family have been found within tumor-derived extracellular vesicles (EVs) such as oncosomes or exosomes. We here investigated the roles of MMP3-rich oncosomes in tumor progression, molecular transmission, and gene regulation. MMP3 and CCN2/CTGF were significantly co-expressed in tumor samples derived from patients suffering from colorectal adenocarcinoma. We found that oncosomes derived from a rapidly metastatic colon cancer cells (LuM1) were enriched in MMP3 and a C-terminal half fragment of CCN2/CTGF. MMP3-rich oncosomes were highly transmissive into recipient cells and were pro-tumorigenic in an allograft mouse model. Oncosome-derived MMP3 was transmissive into recipient cell nuclei, trans-activated CCN2/CTGF promoter, and induced CCN2/CTGF production at 1 to 6 hours after the addition of oncosomes to culture media. In addition, CRISPR/Cas9-mediated knockout of MMP3 showed significant anti-tumor effects, including inhibition of migration and invasion of LuM1 cells in vitro, inhibition of tumor growth in vivo, and reduction of CCN2/CTGF and its promoter activity in vitro. These data newly demonstrate that the oncosome-derived moonlighting metalloproteinase promotes metastasis and is pro-tumorigenic at distant sites as well as a transmissive trans-activator for the cellular communication network gene.

scholarly journals Ccn2 deletion predisposes to aortic aneurysm formation and death in mice which is partially reduced by mineralocorticoid receptor antagonist treatment

2021 ◽  
Author(s):  
Raúl Rodrigues Díez ◽  
Antonio Tejera-Muñoz ◽  
Vanesa Esteban ◽  
Lasse Steffensen ◽  
Raquel Rodrigues-Diez ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Aortic Aneurysm ◽  
Receptor Antagonist ◽  
Mineralocorticoid Receptor ◽  
Transforming Growth Factor ◽  
Ang Ii ◽  
Direct Role ◽  
Mineralocorticoid Receptor Antagonist ◽  
Aneurysm Formation

Background and Purpose: Cellular Communication Network Factor 2 (CCN2) is a matricellular protein normally present in the vascular wall but overexpressed in several cardiovascular diseases. CCN2 has been proposed as a downstream mediator of profibrotic actions of Transforming Growth Factor (TGF)-β and Angiotensin II (Ang II). However, its direct role in cardiovascular diseases is not completely understood. Experimental Approach: To investigate the direct role of CCN2 under vascular pathological conditions, a conditionally deficient CCN2 (CCN2-KO) mouse was evaluated infused or not with Ang II. Key Results: In the absence of CCN2, Ang II infusion induced a rapid (within 48 hours) aortic aneurysm generation and increased aneurysm rupture with 80 % lethality at the endpoint. CCN2 deletion caused elastin layer disruption and increased metalloproteinase activity, which were aggravated by Ang II administration. Aortic RNA-seq studies and the subsequent Gene Ontology enriched analysis pointed out the aldosterone biosynthesis process as one of the most enriched terms in absence of CCN2. Pharmacological aldosterone pathway intervention in Ang II-infused CCN2-KO mice, by treatment with the mineralocorticoid receptor antagonist spironolactone, reduced aneurysm formation and mortality after Ang II infusion. Conclusion and Implications: CCN2 deletion induces a rapid aneurysm formation and rupture after Ang II infusion which is partially prevented by blocking the mineralocorticoid receptor. Our present data highlight, for the first time, the potential role of CCN2 as a vascular homeostatic factor and its relevance in the aldosterone synthesis, opening new avenues to future studies in aortic aneurysm treatment.

scholarly journals Cellular communication network factor 3 in cartilage development and maintenance

2021 ◽  
Author(s):  
Satoshi Kubota ◽  
Harumi Kawaki ◽  
Bernard Perbal ◽  
Kazumi Kawata ◽  
Takako Hattori ◽  
...  
Keyword(s):  
Communication Network ◽  
Cellular Communication ◽  
Cartilage Development ◽  
Cellular Communication Network
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