To determine the impact of progressive elevations in peripheral vascular disease (PVD) risk on microvascular function, we utilized eight rat models spanning “healthy” to “high PVD risk” and used a multi-scale approach to interrogate microvascular function and outcomes. Healthy: Sprague-Dawley rats (SDR), lean Zucker rats (LZR); Mild Risk: SDR on high salt diet (HSD), SDR on high fructose diet (HFD); Moderate Risk: reduced renal mass hypertension (RRM), spontaneously hypertensive rats (SHR); High Risk: obese Zucker rats (OZR) and Dahl salt sensitive rats (DSS). Vascular reactivity and biochemical analyses demonstrated that even mild elevations in PVD risk severely attenuated nitric oxide bioavailability and caused progressive shifts in arachidonic acid metabolism increasing thromboxane A2 levels. With the introduction of hypertension, arteriolar myogenic activation and adrenergic constriction were increased. However, while functional hyperemia and fatigue resistance of in situ skeletal muscle were not impacted with mild or moderate PVD risk, blood oxygen handling suggested an increasingly heterogeneous perfusion within resting and contracting skeletal muscle. Analysis of in situ networks demonstrated an increasingly stable and heterogeneous distribution of perfusion at arteriolar bifurcations with elevated PVD risk; a phenomenon that was manifested first in the distal microcirculation, and evolved proximally with increasing risk. The increased perfusion distribution heterogeneity and loss of flexibility throughout the microvascular network, the result of the combined effects on NO bioavailability, arachidonic acid metabolism, myogenic activation, and adrenergic constriction, may represent the most accurate predictor of the skeletal muscle microvasculopathy and poor health outcomes associated with chronic elevations in PVD risk.