CAREER: Integrating Theory and Experiment to Assess the Contribution of Distinct Vascular Segments in Arterial Insufficiency

Indiana University, Bloomington IN

Investigators

Abstract

Peripheral arterial disease (PAD) is a major health problem that currently affects more than 10 million Americans and that is expected to become even more prevalent with the aging of the population and increased incidence of obesity and diabetes. PAD is caused by a blockage (often due to atherosclerosis) of a major systemic artery such as the femoral artery that supplies blood to the leg. Due to reduced blood and oxygen delivery to their calf and foot, PAD patients often develop pain when walking that progresses to pain at rest and eventual tissue loss, requiring surgical grafts or, in severe cases, amputation. In addition to lost productivity and reduced quality of life for patients, the annual health care costs for PAD are estimated to be 160-300 billion dollars. Currently, only two medications have been approved by the FDA for treating PAD-associated walking impairment, and both treatments are minimally effective. The lack of sufficient data and understanding of the impact of different blood vessel adaptations on restoring normal blood flow following an occlusion motivates this research work. A combined theoretical and experimental model will be used to design more optimal experiments, provide a mechanism for understanding the significance of adaptations to arterial occlusion within distinct vascular segments, and assist in designing more successful PAD therapies. After a major arterial occlusion there is an immediate drop in flow, followed by a short (minutes), steep flow increase and then a gradual (hours to days) flow increase. However, the ability of the vasculature to regulate flow is significantly altered following a major occlusion, preventing full restoration of normal perfusion. Vascular adaptations such as new vessel formation (angiogenesis) and existing vessel growth (arteriogenesis) have been observed to occur in response to a major arterial occlusion, but the relative roles and timing of each adaptation are unclear, making it difficult to extrapolate an optimal strategy for blood flow compensation. In this project, a mathematical model will be developed to predict how short- (acute) and long-term (chronic) vascular adaptations impact flow after a major arterial occlusion. The work will use a multi-scale differential equation model to couple the dynamics of the acute and chronic time scales and to assess the effects of hemodynamic and metabolic stimuli on the collateral and distal microvasculature following an occlusion. Experimental data from the mouse hindlimb will be used to optimize model parameters. To date, no theoretical model has been able to capture both the short and long term dynamics of flow following a major arterial occlusion based on mechanical factors affecting vessel diameter and number. Such work will truly transform the current understanding of peripheral arterial disease by pinpointing the correct targets and timing for therapeutic agents that will help to restore normal perfusion in PAD patients. The project also provides direct exposure of this interdisciplinary research work to high school, undergraduate, and graduate students, thereby promoting the study of STEM disciplines among future generations and enhancing the scientific culture of our nation.