Plasminogen Activator Inhibitor-1 in Systemic Sclerosis: A Nexus of Fibrosis, Vasculopathy, and Senescence.

Abstract

Plasminogen activator inhibitor-1 (PAI-1), a key regulator of the fibrinolytic system, has emerged as a multifaceted contributor to the pathogenesis of systemic sclerosis (SSc). Beyond its classical role in inhibiting plasminogen activation, PAI-1 is implicated in the dysregulation of vascular remodeling, promotion of fibrosis, modulation of immune responses, and the maintenance of cellular senescence-all of which are hallmarks of SSc. Notably, elevated PAI-1 expression has been observed in both patient-derived tissues and experimental models of the disease. Mice deficient in the urokinase-type plasminogen activator receptor (uPAR), which functions with its ligand urokinase-type plasminogen activator (uPA) in the plasminogen activation system, exhibit impaired fibrinolysis and spontaneously develop vasculopathy and fibrosis, closely mirroring human SSc. These findings underscore the pathogenic relevance of the uPA-uPAR-PAI-1 axis in disease progression. Moreover, recent studies suggest that pharmacological inhibition of PAI-1 may not only ameliorate fibrosis and vascular abnormalities but also promote the clearance of senescent cells, thereby interrupting the vicious cycle of chronic inflammation and maladaptive tissue remodeling in SSc. This review highlights the emerging roles of PAI-1 in SSc pathophysiology and explores its potential as a novel therapeutic target for disease modification.