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Humans with a heterozygous loss-of-function\n                    <jats:italic>SERPINE1<\/jats:italic>\n                    variant exhibit protection against aging and cardiometabolic dysfunction. We engineered a mouse model mimicking the human mutation (\n                    <jats:italic>\n                      Serpine1\n                      <jats:sup>TA700\/+<\/jats:sup>\n                    <\/jats:italic>\n                    ) and compared cardiovascular responses with WT littermates.\n                    <jats:italic>Serpine1<\/jats:italic>\n                    <jats:sup>TA700\/+<\/jats:sup>\n                    mice lived 17% longer than did littermate control mice. Under l-N\n                    <jats:sup>G<\/jats:sup>\n                    -nitro-arginine methyl ester\u2013induced (l-NAME\u2013induced) vascular stress,\n                    <jats:italic>\n                      Serpine1\n                      <jats:sup>TA700\/+<\/jats:sup>\n                    <\/jats:italic>\n                    mice exhibited diminished pulse wave velocity (PWV), lower systolic blood pressure (SBP), and preserved left ventricular diastolic function compared with controls. Conversely, PAI-1\u2013overexpressing mice had measurements indicating accelerated cardiovascular aging. Single-cell transcriptomics of\n                    <jats:italic>\n                      Serpine1\n                      <jats:sup>TA700\/+<\/jats:sup>\n                    <\/jats:italic>\n                    aortas revealed a vascular-protective mechanism with downregulation of the extracellular matrix regulators\n                    <jats:italic>Ccn1<\/jats:italic>\n                    and\n                    <jats:italic>Itgb1<\/jats:italic>\n                    .\n                    <jats:italic>\n                      Serpine1\n                      <jats:sup>TA700\/+<\/jats:sup>\n                    <\/jats:italic>\n                    aortas were also enriched in a cluster of smooth muscle cells that exhibited plasticity. Finally, PAI-1 pharmacological inhibition normalized SBP and reversed l-NAME\u2013induced PWV elevation. These findings demonstrate that PAI-1 reduction protects against cardiovascular aging-related phenotypes, while PAI-1 excess promotes vascular pathological changes. Taken together, PAI-1 inhibition represents a promising strategy to mitigate age-related CVD.\n                  <\/jats:p>","DOI":"10.1172\/jci196714","type":"journal-article","created":{"date-parts":[[2025,9,30]],"date-time":"2025-09-30T16:48:21Z","timestamp":1759250901000},"source":"Crossref","is-referenced-by-count":6,"title":["Plasminogen activator inhibitor 1 promotes aortic aging\u2013like pathophysiology in humans and mice"],"prefix":"10.1172","volume":"135","author":[{"given":"Alireza","family":"Khoddam","sequence":"first","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony","family":"Kalousdian","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research Institute,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mesut","family":"Eren","sequence":"additional","affiliation":[{"name":"Feinberg Cardiovascular and Renal Research 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