Progranulin Deficiency Triggers Premature Vascular Aging and Dysfunction
Losing progranulin accelerates vascular senescence, inflammation, and fibrosis—even in young adult mice—linking this protein to early cardiovascular aging.
Resumen
Researchers show that progranulin (PGRN), a multifunctional glycoprotein, acts as a critical brake on vascular aging. In PGRN-deficient mice, blood vessels developed hallmarks of accelerated senescence—inflammation, oxidative stress, fibrosis, and impaired relaxation—even at just 6 months of age. Transcriptomic analysis of vascular smooth muscle cells revealed disrupted mitochondrial function, epigenetic dysregulation, and upregulation of collagen pathways. Senolytic drugs partially rescued endothelial function but paradoxically increased contractility, suggesting distinct roles for endothelial versus smooth muscle cell senescence. In aged mice, PGRN loss worsened vascular and kidney injury without further boosting senescence markers, implying premature rather than progressive senescence. PGRN expression also correlated strongly with the senescence marker p21 in human coronary arteries, underscoring translational relevance.
Resumen detallado
Cardiovascular disease remains the leading cause of global mortality, and vascular aging—driven in part by cellular senescence—is a central mechanism. Senescent cells accumulate in vessel walls over time, secreting pro-inflammatory signals that erode vascular integrity. Understanding which molecular guardians normally prevent this process is critical for developing interventions against early-onset vascular disease.
This study investigated progranulin (PGRN), a secreted glycoprotein involved in inflammation, lysosomal homeostasis, and cellular repair, as a potential regulator of vascular aging. The researchers analyzed PGRN expression in human coronary arteries across age groups and found it increased with aging, strongly correlating with the senescence marker p21. This pattern was recapitulated in mouse aortic tissue, establishing a conserved age-associated PGRN expression profile.
Using global PGRN knockout (PGRN−/−) mice at 6 and 18 months, the team performed wire myography on mesenteric resistance arteries, histological staining, qPCR, western blotting, and RNA sequencing of isolated vascular smooth muscle cells (VSMCs). At just 6 months—considered adult, not aged—PGRN-deficient mice exhibited endothelial dysfunction (impaired acetylcholine-induced relaxation), enhanced vasoconstriction to phenylephrine and U46619, vascular inflammation, and structural remodeling including increased wall cross-sectional area and fibrosis. Senescence markers (SA-β-galactosidase positivity, p21 expression, G2/M cell cycle arrest) were elevated in PGRN−/− VSMCs, confirming premature senescence. Transcriptomic profiling revealed downregulation of oxidative phosphorylation pathways and upregulation of collagen/extracellular matrix genes, alongside epigenetic dysregulation—a signature consistent with the senescence-associated secretory phenotype (SASP).
Senolytic drugs (navitoclax/ABT-263 and fisetin) were administered to 6-month-old PGRN−/− mice to test whether clearing senescent cells could rescue vascular function. Senolytic treatment improved endothelial-dependent relaxation, suggesting that endothelial cell senescence contributes to impaired vasodilation. However, vascular contractility paradoxically increased after treatment, indicating that senescent smooth muscle cells may normally suppress over-contraction—highlighting divergent functional roles of senescence in different vascular cell types. In 18-month-old PGRN−/− mice, vascular dysfunction, fibrosis, and renal injury were significantly worse than in age-matched wild-type controls, yet senescence marker levels did not further increase compared to young PGRN−/− mice. This 'ceiling effect' supports the concept of premature rather than progressive senescence: PGRN loss triggers an early senescent state that plateaus, while cumulative aging adds additional structural damage.
These findings establish PGRN as a novel regulator of vascular homeostasis and suggest that impaired PGRN signaling may predispose individuals to early-onset cardiorenal dysfunction. The human coronary artery data add translational weight, though causality in humans remains to be tested. The study opens avenues for targeting PGRN pathways or downstream senescence mechanisms in cardiovascular disease prevention.
Hallazgos clave
- PGRN expression increases with age in human coronary and mouse arteries and strongly correlates with senescence marker p21.
- PGRN-deficient mice show premature endothelial dysfunction, enhanced vasoconstriction, and vascular fibrosis by 6 months of age.
- RNA-seq of PGRN−/− VSMCs reveals impaired oxidative phosphorylation, epigenetic dysregulation, and collagen pathway upregulation—a senescence signature.
- Senolytic treatment improved endothelial relaxation but increased contractility, revealing divergent roles of endothelial vs. smooth muscle cell senescence.
- Aged PGRN−/− mice showed worsened vascular and renal injury without further senescence marker increases, consistent with premature rather than progressive senescence.
Metodología
The study used global PGRN knockout mice at 6 and 18 months, with wire myography for vascular function, RNA sequencing of isolated VSMCs, histology, qPCR, and western blotting. Senolytic interventions (navitoclax and fisetin, 50 and 100 mg/kg/day respectively, 2 cycles of 5 days on/14 days off) were tested in 6-month-old PGRN−/− mice. Human coronary artery samples from cadaveric donors were used to validate age-associated PGRN and p21 expression.
Limitaciones del estudio
The study relies on global PGRN knockout mice, making it impossible to attribute vascular phenotypes to cell-type-specific PGRN loss without conditional knockouts. Human data are correlational and cross-sectional, precluding causal conclusions. The transcriptomic analysis was performed in cultured VSMCs, which may not fully reflect the in vivo vascular environment.
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