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.
Abdominal aortic aneurysm is the 8th leading cause of death and disability in the United States. Each year, an estimated 30,000 patients die from ruptured aneurysm and another 200,000 new cases are diagnosed. Currently, there is no effective pharmacological therapy to prevent aneurysm from progressing to rupture. Surgical interventions are effective in reducing the risk of rupture, however, are recommended only to patients with aneurysm larger than 5-5.5 cm. Consequently, the majority of aneurysm patients are not currently treated. By exploring how aging of the arterial wall affects aneurysm progression via vascular inflammation, the proposed studies will provide new mechanistic insights regarding disease pathophysiology, knowledge that is fundamental to the development of effective therapeutic strategies for millions of aneurysm patients.
