BackgroundAbdominal aortic aneurysm (AAA) is a potentially life‐threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial.Methods and ResultsWe investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B‐cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B‐cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B‐cell–deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase‐9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin‐6 and metalloproteinase‐9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue.ConclusionsFrom these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue‐destructive activities. Finally, we identified Syk as a potential therapeutic target.

BackgroundAortic dissection (AD) is a life‐threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin‐6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin‐6 in macrophages in pathogenesis of AD.Methods and ResultsWe characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild‐type (WT) mice, but progressed to AD in mice with macrophage‐specific deletion of Socs3 gene (mSocs3‐KO). mSocs3‐KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue‐destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction.ConclusionsThese findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

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Objective: A cardinal feature of Marfan syndrome is thoracic aortic aneurysm. The contribution of the renin-angiotensin system via AT1aR (Ang II [angiotensin II] receptor type 1a) to thoracic aortic aneurysm progression remains controversial because the beneficial effects of angiotensin receptor blockers have been ascribed to off-target effects. This study used genetic and pharmacological modes of attenuating angiotensin receptor and ligand, respectively, to determine their roles on thoracic aortic aneurysm in mice with fibrillin-1 haploinsufficiency ( Fbn1 C1041G/+ ). Approach and Results: Thoracic aortic aneurysm in Fbn1 C1041G/+ mice was found to be strikingly sexual dimorphic. Males displayed aortic dilation over 12 months while aortic dilation in Fbn1 C1041G/+ females did not differ significantly from wild-type mice. To determine the role of AT1aR, Fbn1 C1041G/+ mice that were either +/+ or −/− for AT1aR were generated. AT1aR deletion reduced expansion of ascending aorta and aortic root diameter from 1 to 12 months of age in males. Medial thickening and elastin fragmentation were attenuated. An antisense oligonucleotide against angiotensinogen was administered to male Fbn1 C1041G/+ mice to determine the effects of Ang II depletion. Antisense oligonucleotide against angiotensinogen administration attenuated dilation of the ascending aorta and aortic root and reduced extracellular remodeling. Aortic transcriptome analyses identified potential targets by which inhibition of the renin-angiotensin system reduced aortic dilation in Fbn1 C1041G/+ mice. Conclusions: Deletion of AT1aR or inhibition of Ang II production exerted similar effects in attenuating pathology in the proximal thoracic aorta of male Fbn1 C1041G/+ mice. Inhibition of the renin-angiotensin system attenuated dysregulation of genes within the aorta related to pathology of Fbn1 C1041G/+ mice.

Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and proapoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

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Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.