Cell state transition analysis reveals a causal network that controls critical limb ischemia

Increased endothelial cell (EC) permeability significantly contributes to peripheral arterial disease and its severe manifestation, critical limb ischemia (CLI). CLI remains refractory to current pharmacological interventions, often requiring limb amputation and showing how limited our knowledge is about signaling pathways that control EC states. Here, we utilize a two-pronged approach, employing cell State Transition Assessment and Regulation (cSTAR) analyses to both the published knowledge (e.g., LINCS data portal) and our own transcriptomics data collected from CLI patients and healthy adult (HA) control. We identified CLI and HA transcriptomics patterns and reconstructed causal network that controls transitions between EC states associated with CLI and HA. Contrary to general belief, our study demonstrates that VEGF administration slightly promotes the CLI EC states, indicating VEGF ineffectiveness in enhancing perfusion of CLI tissue. Based on the unveiled control network, we suggest targets whose inhibition would reverse CLI EC states closer to HA states.