Progranulin Functions as an Anti-Vascular Aging Protein by Regulating Mitochondrial Reactive Oxygen Species

Aging is a major and natural cardiovascular risk factor, though the underlying mechanisms remain unclear. The progranulin gene (GRN) encodes progranulin (PGRN) is a glycoprotein with anti-inflammatory properties. Mutations in GRN are linked to severe neurodegenerative disorders. Our group recently demonstrated that PGRN deficiency alters the vascular phenotype of resistance and capacitance arteries, while others have shown that its absence accelerates aging-related cardiac hypertrophy. Here, we explored whether PGRN functions as an anti-aging protein in mitigating vascular dysfunction associated with aging. We first examined PGRN expression in coronary arteries from aged human subjects (both male and female) and aortae from aged male mice, finding significantly elevated PGRN levels alongside increased p21, a marker of cellular senescence or cellular aging. To investigate whether this increase in vascular PGRN expression serves as a protective mechanism, we used 18-month-old wild-type (WT-18) and PGRN-deficient (PGRN KO-18) mice, with 6-month-old mice serving as controls (WT-6 and PGRN KO-6) and analyze the vascular contractility in mesenteric arteries by wire myograph. Compared to WT-6, both PGRN KO-6 and WT-18 exhibited increased contractility in response to phenylephrine (Phe) [Maximal response (mN): WT-6: 8.00±0.36, PGRN KO-6: 9.17±0.28*, WT-18: 9.20±0.44*, p<0.05] and higher vascular p21 accumulation. PGRN KO-18 showed a similar maximal contraction (mN: 8.76±0.31) but demonstrated increased sensitivity to Phe relative to the other groups (pD2: WT-6: 5.06±0.11, PGRN KO-6: 5.08±0.12, WT-18: 5.08±0.12, PGRN KO-18: 6.03±0.11*, *p<0.05). To explore the underlying mechanisms, we performed RNA sequencing on vascular smooth muscle cells (VSMC) from WT and PGRN KO mice, revealing that oxidative stress and oxidative stress-induced senescence pathways were exacerbated in PGRN KO. Additionally, mitochondria in VSMC from PGRN KO were fragmented, accompanied by increased mitochondrial reactive oxygen species (mtROS). Finally, we generated VSMC overexpressing PGRN via lentiviral infection. These cells were protected from irradiation-induced vascular senescence and aging characterized by cell cycle arrest in G1 phase. Our data demonstrate that PGRN limits vascular aging, and that increases in vascular PGRN during aging act as an anti-aging mechanism by restraining mtROS. R01-HL169202-01 and R00-HL14013903 to TBN This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.