Abstract 4367547: Plasminogen Activator Inhibitor-1 Governs Arterial Aging

Abstract

Background: Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1 , contributes to age-related cardiovascular diseases (CVD) and other aging-related pathologies. Humans with a heterozygous loss-of-function SERPINE1 variant exhibit protection against aging and cardiometabolic dysfunction. Hypothesis: Reducing circulating PAI-1 levels protects against vascular stiffening and cardiovascular aging. Methods: We engineered a mouse model mimicking the human mutation ( Serpine1 TA700/+ ) and compared cardiovascular physiologic measures (blood pressure, diastolic function, pulse wave velocity) with wild-type littermates. We collected aortas from Serpine1 TA700/+ mice and wild-type littermate controls for both bulk and single-cell RNA-seq. Results: Serpine1 TA700/+ mice lived 20% longer than littermate controls. Under L-N G -Nitro-arginine methyl ester (L-NAME)-induced vascular stress, Serpine1 TA700/+ mice exhibited lower systolic hypertension (SBP), preserved left ventricular diastolic function, and diminished pulse wave velocity (PWV) compared to controls. Conversely, PAI-1-overexpressing mice exhibited accelerated cardiovascular aging. Single cell transcriptomics of Serpine1 TA700/+ aortas revealed a vascular-protective mechanism with downregulation of extracellular matrix regulators Ccn1 and Itgb1 . Finally, PAI-1 pharmacological inhibition normalized SBP and reversed L-NAME-induced PWV elevation. Conclusions: These findings demonstrate that PAI-1 reduction protects against cardiovascular aging, while PAI-1 excess promotes vascular pathological changes. Taken together, PAI-1 inhibition represents a promising strategy to mitigate age-related CVD.