Impact of the micromechanical environment on inflammation in AAA progression

University Of Wisconsin-Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): Aging is the most important yet least understood risk factor for abdominal aortic aneurysm (AAA), a common, progressive vascular disease with high lethality. The vascular extracellular matrix (ECM) changes with aging, characterized by stiffer and less organized collagen fibers. We hypothesize that these age-related ECM changes predispose older arteries to aneurysm not only by altering vessel mechanical properties but also by influencing the functions of infiltrating inflammatory cells. In this R21, we propose to specifically test how age-related collagen changes affect the inflammatory response during the course of aneurysm development using the transgenic mouse strain Col1a1. The homozygous mutant animals (Col1a1R/R) have been shown to display excessive collagen accumulation and subsequent ECM stiffening as well as exacerbated aneurysm formation. Two Specific Aims are proposed. In Aim 1, we will test whether ECM stiffening accelerates AAA progression and intensifies vascular inflammation by subjecting Col1a1 mutant and wildtype (Col1a1+/+) mice to AAA induction via intraluminal perfusion with elastase (AAA) or heat-inactivated elastase (sham). This so called elastase model is widely accepted for its duplication of major pathological characteristics of human AAAs. We will focus on macrophage-mediated inflammation because macrophages are the predominant type of inflammatory cells found in aneurysmal aorta and are thought to be the major source of elastin degrading proteases. In addition to macrophage recruitment, we will examine macrophage differentiation with the expectation that ECM stiffening facilitates differentiation of the proinflammatory subtype or M1 macrophages or/and suppresses differentiation of the anti-inflammatory subtype or M2 macrophages. Currently, how macrophage subtypes are distributed in aneurysmal tissue and how subtype differentiation may be affected by aging ECM is completely unknown. In Aim 2, we propose culture monocytes (the precursors of macrophages) from wildtype or mutant mice in collagen gels of increasing stiffness to study how collagen-mediated ECM stiffening influences the recruitment and differentiation of inflammatory cells. The results obtained from this study will provide a new concept in understanding aging-associated AAA formation and lay a foundation for future mechanistic studies and drug development. Therefore, our work is significant, novel, and translational.