Differential Myopathic and Transcriptomic Changes in Soleus and Gastrocnemius Muscles in a Novel Chronic Hindlimb Ischemia Rat Model Induced by Endovascular Catheter Occlusion

Peripheral artery disease (PAD) is a progressive atherothrombotic disorder and one of the most prevalent cardiovascular diseases, impacting over 230 million people worldwide. Conventional animal models of chronic hindlimb ischemia (HLI) are highly invasive, technically challenging, do not account for animal-to-animal anatomic variation, fail to occlude collateral vessels, and may not recapitulate progressive disease pathophysiology. To address these limitations, we developed a new chronic HLI model using an Ilio-femoral endovascular catheter occlusion (IFCO) approach. We hypothesized that endovascular occlusion of the iliofemoral artery in rats using an indwelling catheter would chronically reduce hindlimb blood flow, produce PAD-associated myopathy, and overcome limitations of conventional techniques. Time-dependent laser Doppler perfusion imaging demonstrated that IFCO reduced resting hindlimb perfusion for up to 28 days. Histological analysis revealed that IFCO significantly increased levels of fibrosis and decreased myofiber cross-sectional area, in the soleus only. In contrast, HLI in our model increased the proportion of centralized nuclei in both the gastrocnemius and soleus with the soleus exhibiting worse outcomes than the gastrocnemius across all parameters. RNAseq corroborated these findings and showed that the HLI soleus transcriptome was highly fibrotic, pro-angiogenic, and promoted myoblast fusion consistent with the findings of histological myopathy. These data indicate that chronic HLI pathophysiology is different for distinct muscles. This work can help identify the mechanisms responsible for the myopathy of PAD and may inform the design of targeted interventions for the care of PAD patients.