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 S1P 3 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–S1P 3 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.