<i>In vivo</i>, GLP-1 RAs' therapeutic efficacy was significantly weakened in <i>NRP1<sup>EC-KO</sup></i> mice (<i>P</i> < 0.05).<h4>Conclusion</h4>GLP-1 RAs alleviate inflammation and endothelial dysfunction to reduce the atherosclerosis progression by activating the Sema3A/NRP1 pathway and inhibiting downstream ERK1/2-NF-κB signaling. Here, MAPK3 is linked to endothelial dysfunction.