Researchers at Northwestern University demonstrated that PAI-1 (encoded by SERPINE1) is both necessary and sufficient to drive vascular aging. Humans carrying a heterozygous loss-of-function SERPINE1 mutation had significantly lower arterial stiffness (pulse wave velocity) than matched controls. Mice engineered with the same mutation lived 17% longer and were protected against hypertension and aortic stiffening under eNOS-inhibitor stress. Conversely, mice overexpressing a stabilized form of PAI-1 showed accelerated cardiovascular aging. Single-cell transcriptomics revealed that PAI-1 reduction suppresses ECM regulators CCN1 and integrin-β1 and enriches a protective smooth muscle cell population. Pharmacological PAI-1 inhibition normalized blood pressure and reversed stress-induced arterial stiffness, pointing to PAI-1 as a druggable target for age-related cardiovascular disease.
