A key clinical outcome for peripheral vascular disease (PVD) in patients is a poor ability for skeletal muscle to resist fatigue with elevated metabolic demand. Our investigations have revealed that the most commonly interrogated sites of physiological dysfunction (e.g., altered dilator reactivity, endothelial function, constrictor reactivity, etc.) are not robust predictors of poor functional outcomes. Given this, we approached the issue of vasculopathy with elevated PVD risk from the perspective of hemodynamic control and mass transport and exchange using a vertically-integrated, multi-scale approach. These studies build on previous work in the skeletal muscle microcirculation of the obese Zucker rat (OZR) model of the metabolic syndrome to integrate existing knowledge into a greater understanding of the links between impaired muscle perfusion and performance (1). In OZR cremaster muscle, we demonstrated that perfusion distribution at microvascular bifurcations (γ) was consistently more heterogeneous than in controls; increasing from ~0.46-0.54 to ~0.57-0.61 in OZR. Further, this shift in γ was spatially consistent and impacted perfusion distribution throughout the network. However, the underlying mechanistic contributors were spatially divergent as altered adrenergic constriction was the major contributor to altered γ at proximal microvascular bifurcations, and exhibited a steady decay in terms of its significance with longitudinal distance, while endothelial dysfunction was a stronger contributor to altered γ in distal bifurcations with no discernible role proximally (despite the dysfunction being clearly demonstrable). Using measured values of γ, simulations predict that alterations to γ in OZR caused more heterogeneous perfusion distribution in distal arterioles than in controls; an effect that could only be rectified by combined adrenoreceptor blockade and improveed endothelial function. Using tracer washout, we determined that this effect was also demonstrable using the in situ gastrocnemius muscle of OZR. (2,3) To minimize the functional implications of this increased spatial perfusion heterogeneity, a likely compensatory mechanism could be an increased temporal switching at arteriolar bifurcations to minimize downstream perfusion deficits. Using the in situ cremaster muscle, we determined that temporal activity (the cumulative sum of absolute differences between successive values of γ, taken every 20 seconds) was lower in OZR than in control animals, and this difference was present in both proximal (1A-2A) and distal (3A-4A) arteriolar bifurcations. While adrenoreceptor blockade improved temporal activity in 1A-2A arteriolar bifurcations in OZR, this was without impact in the distal microcirculation, where only interventions against oxidant stress and thromboxane A2 were effective. (4) Analysis of the attractor for γ indicated that it was not only elevated in OZR versus controls, but also exhibited reductions in range, indicative of a loss of system flexibility and the ability to adapt to imposed physiological, pharmacological, and/or pathological challenges. It must be noted that these cumulative upstream impairments to hemodynamic control then enter into a capillary network that has experienced a rarefaction of 22-25%, thus further compromising the processes of mass transport/exchange. (5) In our most recent work, we have determined the ultimate hemodynamic consequence of these cumulative upstream perfusion problems, using both the cremaster and gastrocnemius preparations to determine microvascular hematocrit (HMV) in the skeletal muscle of OZR. The use of a multiple tracer washout approach demonstrated that aggregate HMV in OZR skeletal muscle tended to be reduced as compared to controls, although this effect was not pronounced. However, based on an imaging/counting approach in the cremaster muscle, HMV in OZR was demonstrated to be much more variable than in controls, with many capillaries have extremely low hematocrit levels (6). These results suggest that intramuscular perfusion distribution in the OZR model of the metabolic syndrome is altered to result in an extremely variable and excessively stable distribution of blood and erythrocyte flow in the distal microcirculation. Combined with a growing inability of the microcirculation to control its own perfusion in response to any imposed challenge, these may represent increasingly significant contributors to the manifestation of poor muscle performance in this condition.