Time-resolved proteolipidomics of the human aorta identifies stage-specific lipid-protein modules across development...

An established vascular network is a prerequisite to ensuring an optimal supply of oxygen and nutrients for sustaining developmental events and systemic function. Herein, we construct a time-resolved proteolipidomic atlas of the aorta across the human life cycle. trans-omics integration reveals that postnatal ganglioside GM3 accumulation is functionally coregulated with calcium homeostasis mediated by plasma membrane calcium-transporting ATPases (PMCAs). We then verify mechanistically in senescence-induced primary vascular smooth muscle cells (VSMCs) that knockdown of GM3 synthase leads to diminished expressions of both PMCA1 and contractile phenotype marker protein. In aged aortas, defects in branched-chain amino acid catabolism emerge as key adult-to-fetal metabolic reversion, with synchronous reductions in serine-derived lipids, including GM3 and phosphatidylserines. Our work suggests that postnatal increases in aortic GM3s maintain PMCA-regulated calcium homeostasis that delays pathological phenotypic transitions of VSMCs. Reductions in aortic GM3s at old age might cause such adaptations to disintegrate and increase disease susceptibility.