Activating transcription factor-3 orchestrates the modulation of vascular anti-contractile activity and relaxation by governing the secretion of HDL-bound sphingosine-1-phosphate in perivascular adipose tissue

Background and purpose: Perivascular adipose tissues (PVATs) play a critical role in modulating vascular homeostasis and protecting against cardiovascular dysfunction-mediated blood pressure dysregulation. We demonstrated that the activating transcription factor-3 (Atf3) gene in the PVAT is crucial for improving vascular wall tension abnormalities; however, its protective mechanism remains unclear. Herein, we aim to determine whether ATF3 regulates PVAT-derived relaxing factor (PVDRF) biosynthesis and if its secretion contributes to vasorelaxation.

Experimental approach: This study employed an in vivo animal model using global Atf3-deficient mice, in vitro blood vessel myography, and biochemical analyses to evaluate ATF3-mediated PVDRF release and reactivity in the vasculature.

Key results: Wild-type (WT) mouse thoracic aortic PVAT extracts significantly induced resting tone dilation and attenuated vasoconstrictor-induced contractile responses compared to Atf3^-/- mice. Heat-stable PVAT extracts from WT mice caused sustained and reproducible vasodilation without tachyphylaxis in control aortic rings. Biochemical evaluation of PVDRF release revealed that Atf3^-/- mice had lower sphingosine-1-phosphate (S1P) and HDL cholesterol (HDL-C) levels than WT mice. Furthermore, PVAT extracts from WT mice induced long-lasting vasorelaxation, which was significantly inhibited by the S1P₃ receptor antagonist TY52156 and scavenger receptor class B type 1 receptor antagonist glyburide.

Conclusion and implications: ATF3 within the PVAT can modulate vascular function by strengthening sphingosine kinase 1 (sphk1)-S1P-S1P₃ receptor lipid signalling and stimulating S1P binding to HDL to form the vasodilator HDL-S1P. ATF3 is an essential modulator for maintaining the physiological function of PVAT, providing a novel target for treatment of obesity-related cardiovascular diseases.