The authors develop mouse models by mimicking peripheral vascular diseases, combining multiple strategies and transgenic mouse lines, to demonstrate that ECs, but not macrophages or SMCs, play an active role mediated by endothelial ET‐1/neural ETAR signaling and beyond endothelial homeostatic angiocrine by driving protective pain through the endothelial‐neural circuit to alarm the CNS in vascular diseases. This evidence concerns the gene EDNRA and peripheral vascular disease.