Progranulin deficiency induces premature vascular senescence and dysfunction

Cellular senescence-an age-associated state characterized by irreversible cell cycle arrest and proinflammatory signaling-contributes to vascular dysfunction and cardiovascular disease. However, the molecular mechanisms linking senescence to vascular impairment remain incompletely defined. Progranulin (PGRN) is a multifunctional protein involved in inflammation, lysosomal function, and cellular homeostasis, but its role in vascular aging is not well understood. We assessed PGRN expression in human and mouse arteries and in senescent vascular smooth muscle cells (VSMCs). Vascular function was examined in PGRN-deficient (PGRN^-/-) mice. Cellular senescence was pharmacologically targeted using the senolytic agents navitoclax (ABT-263) and fisetin, and vascular phenotypes were evaluated in adult (6-mo-old) and aged (18-mo-old) mice. PGRN expression increased with age in human and mouse arteries and strongly correlated with p21 expression. In adult mice, PGRN deficiency induced endothelial dysfunction, enhanced vasoconstriction, and promoted vascular inflammation and remodeling. Transcriptomic profiling of PGRN^-/- VSMCs revealed a senescence-associated signature characterized by impaired oxidative phosphorylation, epigenetic dysregulation, and enrichment of collagen-related pathways. Senolytic treatment improved endothelial-dependent relaxation but increased vascular contractility in PGRN^-/- mice. In aged mice, PGRN deficiency exacerbated vascular dysfunction, remodeling, and renal injury without further increases in senescence markers, consistent with premature rather than progressive vascular senescence. PGRN deficiency promotes premature vascular dysfunction through coordinated mitochondrial, epigenetic, inflammatory, and structural mechanisms. These findings identify PGRN as a key modulator of vascular homeostasis and suggest that impaired PGRN signaling may predispose to early-onset vascular and cardiorenal dysfunction.NEW & NOTEWORTHY This study identifies progranulin (PGRN) as a key regulator of premature vascular dysfunction. Using human and mouse arteries and integrated multi-omics analyses, we show that PGRN deficiency induces early vascular senescence, mitochondrial dysfunction, epigenetic remodeling, and fibrosis. Senolytic treatment uncovers divergent roles of endothelial versus smooth muscle cell senescence in vascular function, highlighting PGRN as an important modulator of vascular homeostasis during aging.