Cardiovascular Toxicology

, Volume 19, Issue 6, pp 565–574 | Cite as

2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression

  • Mary T. Walsh-Wilcox
  • Joel Kaye
  • Efrat Rubinstein
  • Mary K. WalkerEmail author


2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction.

Graphical Abstract

TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.


Angiotensinogen Cytochrome P4501A1 Perivascular adipose tissue (PVAT) 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) Vascular dysfunction Nitric oxide 



We thank Emily Wheeler and Meera Shah for their expert technical support. This work was support by Teva Pharmaceutical Industries Ltd., Netanya, Israel [DS-2018-003].

Supplementary material

12012_2019_9529_MOESM1_ESM.docx (12 kb)
Supplementary material 1 (DOCX 11 kb)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Mary T. Walsh-Wilcox
    • 1
  • Joel Kaye
    • 2
    • 3
  • Efrat Rubinstein
    • 2
  • Mary K. Walker
    • 1
    Email author
  1. 1.Department of Pharmaceutical Sciences, College of PharmacyUniversity of New Mexico Health Sciences CenterAlbuquerqueUSA
  2. 2.Teva Pharmaceutical Industries LtdNetanyaIsrael
  3. 3.Ayala Targeted TherapiesRehovotIsrael

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