Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation

Abstract

Background Hypertension (HTN) has long been associated with abdominal aortic aneurysm (AAA) development, and these cardiovascular pathologies are biochemically characterized by elevated plasma levels of angiotensin II (AngII) as well as interleukin-6 (IL-6). A biologic relationship between HTN and AAA has not been established, however. Accordingly, the objective of this study was to evaluate whether elevated tension may initiate IL-6 production to accumulate monocyte/macrophages and promote dilation of the abdominal aorta (AA). Methods An IL-6 infusion model (4.36 µg/kg/day) was created utilizing an osmotic infusion pump, and after 4 weeks, AA diameter was measured by digital microscopy. The AA was then excised for CD68 immunostaining and flow cytometric analysis with CD11b and F4/80 to identify macrophages. Aortic segments from wild-type mice were suspended on parallel wires in an ex vivo tissue myograph at experimentally derived optimal tension (1.2 g) and in the presence of elevated tension (ET, 1.7 g) for 3 hr, and expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1) was evaluated by quantitative polymerase chain reaction (QPCR). Isolated aortic vascular smooth muscle cells (VSMCs) were subjected to 12% biaxial cyclic stretch or held static (control) for 3 hr (n = 7), and IL-6 and MCP-1 expressions were evaluated by QPCR. Results Four-week IL-6 infusion resulted in an AA outer diameter that was 72.5 ± 5.6% (P < 0.05) greater than that of control mice, and aortic dilation was accompanied by an accumulation of macrophages in the AA medial layer as defined by an increase in CD68 + staining as well as an increase by flow cytometric quantification of CD11b+/F4/80+ cells. Wild-type AA segments did not respond to ex vivo application of ET but cyclic stretch of isolated VSMCs increased IL-6 (2.03 ± 0.3 fold) and MCP-1 (1.51 ± 0.11 fold) expression compared to static control (P < 0.05). Pretreatment with the selective STAT3 inhibitor WP1066 blunted the response in both cases. Interestingly, AngII did not stimulate expression of IL-6 and MCP-1 above that initiated by tension and again, the response was inhibited by WP1066, supporting an integral role of STAT3 in this pathway. Conclusions An IL-6 infusion model can initiate macrophage accumulation as well as aortic dilation, and under conditions of elevated tension, this proinflammatory cytokine can be produced by aortic VSMCs. By activation of STAT3, MCP-1 is expressed to increase media macrophage abundance and create an environment susceptible to dilation. This biomechanical association between HTN and aortic dilation may allow for the identification of novel therapeutic strategies.

Macrophage-derived netrin-1 promotes abdominal aortic aneurysm formation by activating MMP3 in vascular smooth muscle cells

“…Quantitative RT-PCR revealed that netrin-1 mRNA ( Ntn1 ) expression was significantly increased in AAA aortas compared to healthy tissues exposed to PBS. A similar expression pattern of inflammatory markers adhesion G-protein-coupled receptor E1 ( Adgre1 ), interleukin 6 ( Il6 ) and the C-C motif chemokine 2 ( Ccl2 ) was observed in the aortas, consistent with previous reports 25 (Fig. 1a ).…”

Ying and Yang of Stat3 in pathogenesis of aortic dissection

“…On the other hand, SMCs are resident cells in aortic tissue that are constantly exposed to hemodynamic and humoral stress that may weakly activate the Jak/STAT3 pathway. To support this notion, it has been demonstrated that cyclic stretch of SMCs induced expression of IL-6 [18]. Such a basal activation of STAT3 would be augmented in smSocs3-KO, resulting in the chronic activation of STAT3 as observed in our study.…”

Dynamic transcriptome, accessible genome, and PGR cistrome profiles in the human myometrium

“…The Ingenuity Pathway Analysis (IPA) estimates increased activities of myometrial expansion/remodeling associated TGFβ, PDGF, ERK, and STAT, inflammation management linked TNF and AP‐1, as well as myometrial contraction related p53 signaling, among others (Tables and S4). Changes of these molecular activities appear to be evolutionarily conserved, as evidenced by a similar observation that compares transcriptomic profiles of the mouse myometrium between 18.5 days post coitus and virgin (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE17021, Tables and S5). Notably, majority of the subset of DEGs that match IPA curated glucose downstream targets exhibits changes of gene expression consistent with the response to glucose treatment (Tables , S4 and S5), which suggests relatively higher glucose utilization at the TP stage.…”