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Angiotensin II induces a region-specific hyperplasia of the ascending aorta through regulation of inhibitor of differentiation 3.

ABSTRACT: Angiotensin II (Ang II) has diverse effects on smooth muscle cells (SMCs). The diversity of effects may relate to the regional location of this cell type.The aim of this study was to define whether Ang II exerted divergent effects on smooth muscle cells in the aorta and determine the role of blood pressure and specific oxidant mechanisms.Ang II (1000 ng/kg per minute) infusion for 28 days into mice increased systolic blood pressure and promoted medial expansion of equivalent magnitude throughout the entire aorta. Both effects were ablated by angiotensin II type 1a (AT(1a)) receptor deficiency. Similar increases in systolic blood pressure by administration of norepinephrine promoted no changes in aortic medial thickness. Increased medial thickness was attributable to SMC expansion owing to hypertrophy in most aortic regions, with the exception of hyperplasia of the ascending aorta. Deficiency of the p47(phox) component of NADPH oxidase ablated Ang II-induced medial expansion in all aortic regions. Analysis of mRNA and protein throughout the aorta revealed a much higher abundance of the inhibitor of differentiation 3 (Id3) in the ascending aorta compared to all other regions. A functional role was demonstrated by Id3 deficiency inhibiting Ang II-induced SMC hyperplasia of the ascending aorta.In conclusion, Ang II promotes both aortic medial hypertrophy and hyperplasia in a region-specific manner via an oxidant mechanism. The ascending aortic hyperplasia is dependent on Id3.

SUBMITTER: Owens AP

PROVIDER: S-EPMC2825288 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

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Angiotensin II induces a region-specific hyperplasia of the ascending aorta through regulation of inhibitor of differentiation 3.

Owens A Phillip AP Subramanian Venkateswaran V Moorleghen Jessica J JJ Guo Zhenheng Z McNamara Coleen A CA Cassis Lisa A LA Daugherty Alan A

Circulation research 20091217 3

<h4>Rationale</h4>Angiotensin II (Ang II) has diverse effects on smooth muscle cells (SMCs). The diversity of effects may relate to the regional location of this cell type.<h4>Objective</h4>The aim of this study was to define whether Ang II exerted divergent effects on smooth muscle cells in the aorta and determine the role of blood pressure and specific oxidant mechanisms.<h4>Methods and results</h4>Ang II (1000 ng/kg per minute) infusion for 28 days into mice increased systolic blood pressure ...[more]

PMID: 20019328

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Project description:ObjectiveOsteoclastogenic activation of macrophages (OCG) occurs in human abdominal aortic aneurysms (AAAs) and in calcium chloride-induced degenerative AAAs in mice, which have increased matrix metalloproteinase activity. As the activity of OCG in dissecting aneurysms is not clear, we tested the hypothesis that OCG contributes to angiotensin II (Ang II)-induced dissecting aneurysm (Ang II-induced AAA) in apolipoprotein E knockout mice.MethodsAAAs were produced in apolipoprotein E knockout mice via the administration of Ang II. Additionally, receptor activator of nuclear factor kB ligand (RANKL)-neutralizing antibody (5 mg/kg) was administered to one group of mice 7 days prior to Ang II infusion. Aneurysmal sections were probed for presence of RANKL and tartrate-resistant acid phosphatase via immunohistochemistry and immunofluorescence staining. Mouse aortas were also examined for RANKL and matrix metalloproteinase 9 expression via Western blot. In vitro murine vascular smooth muscle cells (MOVAS) and murine macrophages (RAW 264.7) were analyzed for the expression of osteogenic factors via Western blot, qPCR, and flow cytometry in response to Ang II or RANKL stimulation. The signaling pathway that mediates Ang II-induced RANKL expression in MOVAS cells was also investigated via application of TG101348, a Janus kinase 2 (JAK2) inhibitor, and Western blot analysis.ResultsImmunohistochemical staining of Ang II-induced AAA sections revealed OCG as evidenced by increased RANKL and tartrate-resistant acid phosphatase expression compared with control mice. Immunofluorescence staining of AAA sections revealed co-localization of vascular smooth muscle cells and RANKL, revealing vascular smooth muscle cells as one potential source of RANKL. Systemic administration of RANKL-neutralizing antibody suppressed Ang II-induced AAA, with significant reduction of the maximum diameter of the abdominal aorta compared with vehicle controls (1.5 ± 0.4 mm vs 2.2 ± 0.2 mm). Ang II (1 μM) treatment induced a significant increase in RANKL messenger RNA expression levels in MOVAS cells compared with the vehicle control (1.0 ± 0.2 vs 2.8 ± 0.2). The activities of JAK2 and signal transducer and activator of transcription 5 (STAT5) were also significantly increased by Ang II treatment. Inhibition of JAK2/STAT5 suppressed Ang II-induced RANKL expression, suggesting the involvement of the JAK2/STAT5 signaling pathway.ConclusionsOCG with increased RANKL expression was present in Ang II-induced AAA, and neutralization of RANKL suppressed AAA formation. As neutralization of RANKL has been used clinically to treat osteoporosis and other osteoclast-related diseases, additional study of the effectiveness of RANKL neutralization in AAA is warranted.

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Angiotensin II induces a region-specific hyperplasia of the ascending aorta through regulation of inhibitor of differentiation 3.

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Angiotensin II induces a region-specific hyperplasia of the ascending aorta through regulation of inhibitor of differentiation 3.

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