Noncanonical Thyroid Hormone Receptor α Action Mediates Arterial Vasodilation

Abstract

Abstract Context Hypothyroidism impairs cardiovascular health and contributes to endothelial dysfunction with reduced vasodilation. How 3,5,3′-triiodothyronine (T3) and its receptors are involved in the regulation of vasomotion is not yet fully understood. In general, thyroid hormone receptors (TRs) either influence gene expression (canonical action) or rapidly activate intracellular signaling pathways (noncanonical action). Objective Here we aimed to characterize the T3 action underlying the mechanism of arterial vasodilation and blood pressure (BP) regulation. Methods Mesenteric arteries were isolated from male rats, wild-type (WT) mice, TRα knockout (TRα 0) mice, and from knockin mice with a mutation in the DNA-binding domain (TRα GS). In this mutant, DNA binding and thus canonical action is abrogated while noncanonical signaling is preserved. In a wire myograph system, the isolated vessels were preconstricted with norepinephrine. The response to T3 was measured, and the resulting vasodilation (Δ force [mN]) was normalized to maximum contraction with norepinephrine and expressed as percentage vasodilation after maximal preconstriction with norepinephrine (%NE). Isolated vessels were treated with T3 (1 × 10–15 to 1 × 10–5 mol/L) alone and in combination with the endothelial nitric oxide–synthase (eNOS) inhibitor L-NG-nitroarginine methyl ester (L-NAME) or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The endothelium was removed to determine the contribution of T3 to endothelium-dependent vasodilation. The physiological relevance of T3-induced vasodilation was determined by in vivo arterial BP measurements in male and female mice. Results T3 treatment induced vasodilation of mesenteric arteries from WT mice within 2 minutes (by 21.5 ± 1.7%NE). This effect was absent in arteries from TRα 0 mice (by 5.3 ± 0.6%NE, P < .001 vs WT) but preserved in TRα GS arteries (by 17.2 ± 1.1%NE, not significant vs WT). Inhibition of either eNOS or PI3K reduced T3-mediated vasodilation from 52.7 ± 4.5%NE to 28.5 ± 4.1%NE and 22.7 ± 2.9%NE, respectively. Removal of the endothelium abolished the T3-mediated vasodilation in rat mesenteric arteries (by 36.7 ± 5.4%NE vs 3.5 ± 6.2%NE). In vivo, T3 injection led to a rapid decrease of arterial BP in WT (by 13.9 ± 1.9 mm Hg) and TRα GS mice (by 12.4 ± 1.9 mm Hg), but not in TRα 0 mice (by 4.1 ± 1.9 mm Hg). Conclusion These results demonstrate that T3 acting through noncanonical TRα action affects cardiovascular physiology by inducing endothelium-dependent vasodilation within minutes via PI3K and eNOS activation.