British journal of pharmacology · 2025
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.
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Li Hsiao-Fen, Lin Heng, Liu Hsin-Tzu, Lin Tsung-Jen, Tseng Tzu-Ling
Аннотация
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.
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.