Progranulin deficiency induces premature vascular senescence and dysfunction

Area of Science:

• Cardiovascular Biology
• Aging Research
• Molecular Medicine

Background:

• Cellular senescence drives vascular dysfunction and cardiovascular disease.
• Molecular links between senescence and vascular aging are not fully understood.
• Progranulin's (PGRN) role in vascular aging requires investigation.

Purpose of the Study:

• To investigate the role of Progranulin (PGRN) in vascular aging and senescence.
• To elucidate the molecular mechanisms by which PGRN influences vascular homeostasis.
• To assess the impact of PGRN deficiency on vascular function and senescence.

Main Methods:

• Assessed PGRN expression in human and mouse arteries and senescent vascular smooth muscle cells (VSMCs).
• Evaluated vascular function in Progranulin-deficient (PGRN⁻/⁻) mice.
• Utilized senolytic agents (navitoclax, fisetin) to target cellular senescence and assessed vascular phenotypes in adult and aged mice.

Main Results:

• PGRN expression increased with age and correlated with p21 expression in arteries.
• PGRN deficiency in adult mice caused endothelial dysfunction, increased vasoconstriction, inflammation, and remodeling.
• Transcriptomic analysis of PGRN⁻/⁻ VSMCs revealed senescence signatures involving mitochondrial dysfunction, epigenetic changes, and collagen pathways.
• Senolytic treatment had mixed effects in PGRN⁻/⁻ mice, improving relaxation but increasing contractility.
• In aged mice, PGRN deficiency worsened vascular and renal dysfunction, suggesting premature vascular senescence.

Conclusions:

• Progranulin (PGRN) deficiency promotes premature vascular dysfunction via mitochondrial, epigenetic, inflammatory, and structural mechanisms.
• PGRN is a key regulator of vascular homeostasis.
• Impaired PGRN signaling may contribute to early-onset vascular and cardiorenal dysfunction.