Thrombospondin-1, Free Radicals, and the Coronary Microcirculation: The Aging Conundrum

Significance: Successful matching of cardiac metabolism to perfusion is accomplished primarily through vasodilation of the coronary resistance arterioles, but the mechanism that achieves this effect changes significantly as aging progresses and involves the contribution of reactive oxygen species (ROS). Recent Advances: A matricellular protein, thrombospondin-1 (Thbs-1), has been shown to be a prolific contributor to the production and modulation of ROS in large conductance vessels and in the peripheral circulation. Recently, the presence of physiologically relevant circulating Thbs-1 levels was proven to also disrupt vasodilation to nitric oxide (NO) in coronary arterioles from aged animals, negatively impacting coronary blood flow reserve. Critical Issues: This review seeks to reconcile how ROS can be successfully utilized as a substrate to mediate vasoreactivity in the coronary microcirculation as normal'' aging progresses, but will also examine how Thbs-1-induced ROS production leads to dysfunctional perfusion and eventual ischemia and why this is more of a concern in advancing age. Future Directions: Current therapies that may effectively disrupt Thbs-1 and its receptor CD47 in the vascular wall and areas for future exploration will be discussed.