Gender differences in rodent experimental abdominal aortic aneurysm development: Focusing on gonadal hormone regulation, chemokine and cytokine expression, leukocyte recruitment, matrix metalloproteinase activity, extracellular matrix protein degradation and synthesis, and treatment using a dendrimer-based system.

Abstract

Abdominal aortic aneurysms (AAAs) are one of the leading causes of death in the United States each year. Although many patients require elective or emergent surgical repair of AAAs, there are presently no effective medical therapies to treat patients with AAAs. Epidemiological studies have shown that males form AAAs four times more often than females. The mechanical and molecular mechanisms behind this observation are unknown. The present study hypothesizes that gender-related differences in aortic aneurysm formation are driven by hormonal regulation of the inflammatory response in the aortic wall, and it is the balance between extracellular matrix (ECM) proteins and enzymes that degrade them, namely matrix metalloproteinases (MMPs) that is critical. Although it is clear that aortic elastin concentration is markedly reduced through a loss of the internal elastic lamellae and other elastin components of the aortic media in AAAs, it is debated whether the collagen concentration in AAAs is decreased, unchanged, or increased, compared to normal aortic tissue. Initially, gender-based differences in aortic tensile strength, ECM proteins, and MMPs between native male and female rats were examined to determine if inherent differences in mechanical properties, proteins, enzymes, and/or hormone levels favor the formation of aneurysms in males compared to females. Following experiments on aorta, the second aim involved the induction of an experimental AAA in a rodent model in which alterations in tensile strength, ECM proteins, and MMPs were tracked in control (salinetreated) and aneurysmal (elastase-treated) aortas of male and female rats. Additionally, the effects of hormonal and surgical gender manipulations on AAA formation and leukocyte recruitment were investigated, to provide insight into the reasons males are more susceptible to AAA formation compared to females. Upon completion of these experiments, potential therapeutic agents which inhibit or slow the growth of experimental aneurysms in male rodents were selected. Finally, using experimental approaches, a drug delivery vehicle was developed to target tissue in normal and aneurysmal aortas. In conjunction with these experiments, the transport of these nano-scale dendrimers through aortic tissue was modeled theoretically.