Abstract Body (Do not enter title and authors here): 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.