{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:01:47Z","timestamp":1783036907145,"version":"3.54.6"},"reference-count":71,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Perivascular adipose tissues (PVATs) play a critical role in modulating vascular homeostasis and protecting against cardiovascular dysfunction\u2010mediated blood pressure dysregulation. We demonstrated that the activating transcription factor\u20103 (<jats:italic>Atf3<\/jats:italic>) 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\u2010derived relaxing factor (PVDRF) biosynthesis and if its secretion contributes to vasorelaxation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>This study employed an in vivo animal model using global <jats:italic>Atf3<\/jats:italic>\u2010deficient mice, in vitro blood vessel myography, and biochemical analyses to evaluate ATF3\u2010mediated PVDRF release and reactivity in the vasculature.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Wild\u2010type (WT) mouse thoracic aortic PVAT extracts significantly induced resting tone dilation and attenuated vasoconstrictor\u2010induced contractile responses compared to <jats:italic>Atf3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Heat\u2010stable PVAT extracts from WT mice caused sustained and reproducible vasodilation without tachyphylaxis in control aortic rings. Biochemical evaluation of PVDRF release revealed that <jats:italic>Atf3<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice had lower sphingosine\u20101\u2010phosphate (S1P) and HDL cholesterol (HDL\u2010C) levels than WT mice. Furthermore, PVAT extracts from WT mice induced long\u2010lasting vasorelaxation, which was significantly inhibited by the S1P<jats:sub>3<\/jats:sub> receptor antagonist TY52156 and scavenger receptor class B type 1 receptor antagonist glyburide.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>ATF3 within the PVAT can modulate vascular function by strengthening sphingosine kinase 1 (sphk1)\u2013S1P\u2013S1P<jats:sub>3<\/jats:sub> receptor lipid signalling and stimulating S1P binding to HDL to form the vasodilator HDL\u2010S1P. ATF3 is an essential modulator for maintaining the physiological function of PVAT, providing a novel target for treatment of obesity\u2010related cardiovascular diseases.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.17433","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T01:54:00Z","timestamp":1737597240000},"page":"1763-1782","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Activating transcription factor\u20103 orchestrates the modulation of vascular anti\u2010contractile activity and relaxation by governing the secretion of HDL\u2010bound sphingosine\u20101\u2010phosphate in perivascular adipose tissue"],"prefix":"10.1111","volume":"182","author":[{"given":"Hsiao\u2010Fen","family":"Li","sequence":"first","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine Taipei Medical University  Taipei 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