Plasminogen Activator Inhibitor-1 promotes aortic aging-1 like pathophysiology in humans and mice

36 Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, contributes to age-related 37 cardiovascular diseases (CVD) and other aging-related pathologies. Humans with a heterozygous 38 loss-of-function SERPINE1 variant exhibit protection against aging and cardiometabolic 39 dysfunction. We engineered a mouse model mimicking the human mutation (Serpine1 TA700/+) and 40 compared cardiovascular responses with wild-type littermates. Serpine1 TA700/+ mice lived 20% 41 longer than littermate controls. Under L-N G-Nitro-arginine methyl ester (L-NAME)-induced 42 vascular stress, Serpine1 TA700/+ mice exhibited diminished pulse wave velocity (PWV), lower 43 systolic hypertension (SBP), and preserved left ventricular diastolic function compared to controls. 44 Conversely, PAI-1-overexpressing mice exhibited measurements indicating accelerated 45 cardiovascular aging. Single cell transcriptomics of Serpine1 TA700/+ aortas revealed a vascular-46 protective mechanism with downregulation of extracellular matrix regulators Ccn1 and Itgb1. 47 Serpine1 TA700/+ aortas were also enriched in a cluster of smooth muscle cells that exhibited 48 plasticity. Finally, PAI-1 pharmacological inhibition normalized SBP and reversed L-NAME-49 induced PWV elevation. These findings demonstrate that PAI-1 reduction protects against 50 cardiovascular aging-related phenotypes, while PAI-1 excess promotes vascular pathological 51 changes. Taken together, PAI-1 inhibition represents a promising strategy to mitigate age-related 52 CVD. 53