Progranulin sustains the anti-contractile properties of PVAT by preserving the mitochondrial respiration and browning phenotype in a PPARγ-dependent manner

Perivascular adipose tissue (PVAT) surrounds blood vessels and plays a crucial role in regulating vascular tone. Under normal conditions, aortic PVAT exhibits a browning phenotype; however, in diseases such as obesity and hypertension, PVAT transitions to a white phenotype, losing its anti-contractile function through mechanisms that remain unclear. Progranulin (PGRN), an anti-inflammatory protein whose mutation is linked to neurodegenerative diseases, has recently been shown to influence mitochondrial quality and vascular function. Whether PGRN also regulates PVAT quality and function is unknown. Here, we hypothesized that PGRN deficiency induces a whitening phenotype and dysfunction of PVAT by suppressing peroxisome proliferator-activated receptor gamma (PPARγ) signaling and mitochondrial respiration. We used male PGRN global knockout mice (PGRN KO) and wild-type (WT) controls to assess the quality and function of aortic PVAT. In wire myograph experiments, no differences were observed in KCl and phenylephrine (Phe) responses. However, PVAT from WT mice suppressed the Phe response, while PVAT from PGRN KO mice did not, suggesting that PGRN is critical for maintaining the anti-contractile effect of PVAT. Additionally, PVAT from PGRN KO mice exhibited a whitening phenotype, reduced mitochondrial respiration (measured using the Oroboros 2k respirometry system in isolated mitochondria), and decreased nitric oxide (NO) production (measured via DAF-2). To investigate if PVAT dysfunction was driven by the whitening phenotype, we restored the browning feature by treating PGRN KO mice with a β3-adrenergic agonist (CL316243, 1 mg/kg/day) for 1 week, which reversed the whitening phenotype, restored mitochondrial respiration, and reinstated the anti-contractile effect of PVAT. Furthermore, PGRN KO mice exhibited reduced PPARγ expression, which is known to regulate mitochondrial function and brown adipocyte biogenesis. Treatment with the PPARγ activator pioglitazone (20 mg/kg/day for 1 week) also reversed the whitening phenotype, restored mitochondrial respiration, and recovered the anti-contractile function of PVAT in PGRN KO mice. In vitro, 3T3-L1 pre-adipocytes overexpressing PGRN (highPGRN) or silenced for PGRN (PGRN shRNA) showed that PGRN overexpression increased brown adipocyte markers ( PGC1α, UCP1, and CIDEA ) and PPARγ expression, whereas PGRN silencing reduced these markers. These findings suggest that PGRN is essential for maintaining the browning phenotype of PVAT by regulating PPARγ signaling, which in turn impacts mitochondrial respiration, nitric oxide production, and the anti-contractile effect of PVAT. Future studies are needed to explore the role of PGRN in PVAT dysfunction in diseases such as obesity and hypertension. R01-HL169202-01 and R00-HL14013903 to TB and AHA-23DIVSUP1069230 to RMC 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.