Microvascular dynamics regulate post-ischemic muscle damage and regeneration in experimental hindlimb ischemia

Abstract

Tissue microvasculature is known to remodel in response to ischemia. Yet, how this remodeling contributes to the process of post-ischemic recovery is still not completely understood. We studied how microvascular changes relate to post-ischemic muscle repair. Muscle-level microvascular alterations of blood flow and hemoglobin oxygenation, and post-ischemic myofiber and capillary responses were analyzed in aged, healthy C57Bl/6J mice (n = 48) and aged, hyperlipidemic LDLR−/−ApoB100/100 mice (n = 69) after induction of acute hindlimb ischemia using contrast ultrasound, photoacoustic imaging, and histological analyses, respectively. Microvascular responses leading to successful post-ischemic muscle repair in C57Bl/6J mice included an early capillary dilation phase preceding the return of arterial driving pressure followed by an increase in capillary density that further supported satellite cell-induced muscle regeneration. Failure of initial capillary enlargement due to a life-long moderate hypercholesterolemia in LDLR−/−ApoB100/100 mice led to inability to recover arterial driving pressure and resulted in an increase in distal necrosis, chronic tissue damage and a delay in overall recovery after ischemia. To conclude, these data reveal the important role of transient capillary enlargement in initiating a cascade of capillary events that are crucial for a successful post-ischemic muscle recovery. Essentially, the observed dynamic nature of the post-ischemic capillaries should be considered when designing novel treatments targeting the microvasculature in ischemic diseases.