Blood Flow Control During Ischemic Revascularization

Abstract

Control of blood flow to skeletal muscle is essential to maintain the overall homeostasis of an organism. The primary route that skeletal muscle uses to accommodate an increased metabolic demand associated with physical activity is to increase its blood flow through functional hyperemia. The importance of functional hyperemia in ensuring proper skeletal muscle function spurred 130 years of investigation into the mechanism(s) regulating its occurrence.Despite not identifying the essential factor(s) for controlling skeletal muscle blood flow, the last century of investigation has uncovered much about the process; including the observation that skeletal muscle functional hyperemia is impaired with ischemic disease. In patients, this can result in immobility, chronic ulcerations, gangrene, and at worst, amputation. To develop efficacious therapies, we as scientists must develop a better understanding of the molecular mechanisms underlying impaired vascular function during ischemia.The goal of this work was to lay the foundation for investigations examining the role of specific gene products involved in modulating blood flow control during ischemic revascularization by assessing vascular function in the mouse following an ischemic event. Unique among research animals, the mouse is routinely accessible for targeted genetic disruption, which allows investigators to assess the requirement of specific gene-products in a physiological process. Unfortunately, to date, no publication that I am aware of describes blood flow measurement to contracting mouse skeletal muscle following an ischemic/revascularization event. Therefore, the primary objective of this work was to assess vascular function in genetically unaltered animals.I found that unlike other species thus far examined, vascular dysfunction is not an obligatory response to hindlimb ischemic revascularization in the mouse. Ex vivo vasodilation responses to acetylcholine were statistically significantly impaired in the muscular branch artery 14 days following an ischemic event. However, using a newly developed fluorescent microsphere-based approach for determining skeletal muscle blood flow, I found that functional hyperemia was similar for the gracilis posterior muscle between non-ischemic and day-14 ischemic animals. In light of the primary literature, these findings suggest that vascular growth, and not ischemia per se is the primary regulator of vascular function during health and disease.