TUG-891-mediated FFAR4 activation attenuates vascular remodeling via suppression of aberrant browning and lipolysis in perivascular adipose tissue.

Background

Free fatty acid receptor 4 (FFAR4) activation modulates adipogenesis, but this pathway has not been explored in the context of perivascular adipose tissue (PVAT) dysfunction and vascular remodeling.

Methods

Adipose tissue-specific FFAR4 knockout (Adipo-Ffar4-/-, Adipo-KO) mice were generated by crossing Adipoq-Cre and Ffar4flox/flox (WT) mice. FeCl₃-induced PVAT injury model in abdominal aorta was established. TUG-891 (20 mg/kg/day, i.p.) was administered for 4 weeks. In vitro, FeCl₃-conditioned medium was prepared with mouse PVAT explants. Proliferation and migration of vascular smooth muscle cells (VSMCs) cultured with conditioned medium were assessed.

Results

FFAR4 was particularly upregulated in abdominal aortic PVAT in response to high-fat diet. TUG-891-mediated FFAR4 activation in PVAT alleviated abdominal aortic dysfunction and hyperplasia in WT mice. TUG-891 also prohibited aberrant lipolysis and browning, as evidenced by lower serum FFA levels and downregulated UCP1 expression, in a FFAR4-dependent manner. Expression of pro-remodeling genes (CCL2, MMP9, SPP1) in damaged PVAT was reduced by TUG-891. These protective effects were absent in Adipo-KO mice. In vitro, conditioned medium from FeCl₃-primed PVAT promoted VSMC proliferation and migration, which was attenuated by TUG-891 in the presence of FFAR4. Free fatty acids also enhanced VSMC proliferation and migration. These effects were abolished when using PVAT or cells from Adipo-KO mice.

Conclusion

These results indicate that TUG-891 mitigates vascular hyperplasia and remodeling by activating FFAR4 in PVAT, reducing lipolysis and suppressing aberrant adipocyte browning. Targeting PVAT FFAR4 signaling may represent a promising therapeutic strategy for vascular diseases.