We found that Fc-ELA-21 significantly improved cardiac systolic dysfunction, mitigated pulmonary congestion, slowed down weight gain, activated vascular endothelial growth factor receptor 3 (VEGFR3) and APJ-mediated extracellular signal-regulated kinase (ERK) 1/2 signaling, and promoted endothelial cell proliferation in post-infarct mice. Here, APLNR is linked to pulmonary vascular congestion.