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

Area of Science:

• Cardiovascular Biology
• Biomedical Engineering
• Molecular Medicine

Background:

• Hypertension (HTN) is linked to abdominal aortic aneurysm (AAA) development, with elevated angiotensin II (AngII) and interleukin-6 (IL-6) in circulation.
• A direct biological link between HTN and AAA pathogenesis remains unestablished.
• This study investigates if elevated mechanical tension initiates IL-6 production, promoting macrophage accumulation and aortic dilation.

Purpose of the Study:

• To determine if elevated tension in the abdominal aorta (AA) can induce interleukin-6 (IL-6) production.
• To assess if IL-6 infusion promotes macrophage accumulation and aortic dilation.
• To elucidate the role of vascular smooth muscle cells (VSMCs) and STAT3 in tension-induced inflammatory responses.

Main Methods:

• An IL-6 infusion model in mice was used to measure AA diameter and macrophage infiltration via CD68 staining and flow cytometry.
• Ex vivo myography assessed the response of wild-type aortic segments to optimal and elevated tension (ET), measuring IL-6 and monocyte chemoattractant protein-1 (MCP-1) expression via quantitative polymerase chain reaction (QPCR).
• Isolated VSMCs were subjected to cyclic stretch or static conditions, with IL-6 and MCP-1 expression analyzed by QPCR, and the effect of a STAT3 inhibitor (WP1066) was evaluated.

Main Results:

• IL-6 infusion significantly increased AA diameter by 72.5% and led to macrophage accumulation in the aortic media.
• Ex vivo elevated tension did not affect aortic segments, but cyclic stretch of isolated VSMCs significantly increased IL-6 and MCP-1 expression.
• STAT3 activation was critical, as the STAT3 inhibitor WP1066 blunted the response to cyclic stretch and tension-induced IL-6/MCP-1 expression; AngII did not stimulate these factors.

Conclusions:

• Interleukin-6 (IL-6) infusion models can induce macrophage accumulation and aortic dilation.
• Elevated mechanical tension stimulates aortic VSMCs to produce IL-6 via STAT3 activation.
• This biomechanical pathway, involving STAT3-mediated MCP-1 expression and macrophage accumulation, contributes to aortic dilation and suggests novel therapeutic targets for HTN-associated AAA.