Progranulin deficiency aggravates aging-induced vascular injury

  1. Renata de Azevedo Melo Luvizotto
  2. Andre F Nascimento
  3. Gustavo F Pimenta
  4. Rafael M Costa
  5. Shubhnita Singh
  6. Juliano V Alves
  7. Wanessa Awata
  8. Angela Russ
  9. Adeyeye Haastrup
  10. Rolando Cuevas
  11. Parya Behzadi
  12. Cynthia St Hilaire
  13. Justin Roberts
  14. Ariane Bruder
  15. Thiago Bruder-Nascimento
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Abstract

Significance

Vascular aging is a major contributor to cardiovascular disease, yet the molecular mechanisms of age-associated vascular dysfunction remain incompletely defined. This study reveals a critical role for progranulin (PGRN) in regulating vascular senescence, function, and remodeling during aging.

Methods

We assessed PGRN expression in human and mouse arteries and senescent vascular smooth muscle cells (VSMCs). Functional vascular studies were performed in PGRN-deficient (PGRN⁻/⁻) mice. Senescence was modulated pharmacologically using the senolytic agent navitoclax (ABT-263), and vascular phenotype was evaluated in adult (6-month-old) and aged mice (18-month-old).

Results

PGRN expression increased with age in human and mouse arteries, correlating with elevated p21 expression. PGRN deficiency in adult mice induced endothelial dysfunction, increased vasoconstriction, and induced vascular inflammation and remodeling. Transcriptomic analysis of PGRN⁻/⁻ VSMCs revealed a senescence-associated signature, including perturbed oxidative phosphorylation, altered epigenetic regulation, and collagen pathways. Pharmacological clearance of senescent cells improved endothelial function but increased vascular contractility in PGRN⁻/⁻ mice. In aged mice, PGRN deficiency aggravated vascular dysfunction, remodeling, and renal injury without further increasing senescence markers—suggesting premature, rather than progressive, senescence in the PGRN⁻/⁻ mice.

Conclusion

PGRN is a novel regulator of vascular aging, coordinating senescence, inflammation, and remodeling. While endothelial senescence contributes to dysfunction, VSMCs senescence may serve an adaptive role in modulating vascular tone. Targeting PGRN or senescence pathways may offer therapeutic opportunities for age-related vascular diseases, especially in patients with PGRN mutations associated with frontotemporal dementia.

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