INFLAMMATORY MACROPHAGE REGULATION OF ANGIOGENESIS AND SKELETAL MUSCLE PHENOTYPES

Abstract

Chronic inflammation is a hallmark of cardiovascular disease; however, there is a lack of understanding of how systemic inflammation affects the peripheral skeletal muscle to potentially hasten frailty and functional declines in patients. The overarching objective of this dissertation was to determine whether this systemic inflammation is accompanied by macrophage infiltration of skeletal muscle and reductions in skeletal muscle capillarization and fiber size. Using animal models of a) heart failure (HF) induced by transverse aortic constriction (TAC), and b) skeletal muscle ischemia, this work illuminates changes that occur in skeletal muscle with cardiovascular disease-related inflammation. The first study demonstrated that pressure overload resulted in cardiac hypertrophy in male rats consistent with heart failure with preserved ejection fraction (HFpEF), while females did not show cardiac hypertrophy or HF. The second study demonstrated sex-specific differences in skeletal muscle, with TAC male rats exhibiting smaller fiber sizes and greater capillarization, and female TAC rats exhibiting lower capillarization than Sham counterparts. This study then investigated skeletal muscle macrophages to determine whether they might underly or contribute to these differences. There were fewer macrophages in the skeletal muscle of male TAC rats than male Sham rats, and macrophage conditioned medium from TAC rats produced less-developed capillary networks in an ex vivo, experimental assay. Finally, the third study investigated whether an acute bout of systemic inflammation, in the absence of HF, could alter the infiltration of macrophages, or skeletal muscle fiber size or capillarization. Hindlimb ischemia was used to induce acute, systemic inflammation that peaked after 1 day. This systemic inflammation increased the infiltration of macrophages into remote, non-ischemic skeletal muscle by day 7; however, muscle structure was preserved over this short time course. This dissertation demonstrates that cardiovascular disease-associated inflammation is linked with tissue-level changes in macrophages in a sex-specific manner. These changes accompany and may, over time, contribute to skeletal muscle fiber atrophy and changes in capillarization in cardiovascular disease patients.