Noncanonical Thyroid Hormone Receptor α Action Mediates Arterial Vasodilation

Context: Hypothyroidism impairs cardiovascular health and contributes to endothelial dysfunction with reduced vasodilation. How 3,5,3'-triiodothyronine (T-3) 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 T-3 action underlying the mechanism of arterial vasodilation and blood pressure (BP) regulation. Methods: Mesenteric arteries were isolated from male rats, wild-type (WT) mice,TR alpha knockout (TR alpha(0)) mice, and from knockin mice with a mutation in the DNA-binding domain (TR alpha(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 T-3 was measured, and the resulting vasodilation (Delta 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 T-3 (1 x 10(-15) to 1 x 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 T-3 to endothelium-dependent vasodilation. The physiological relevance of T-3-induced vasodilation was determined by in vivo arterial BP measurements in male and female mice. Results: T-3 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 TR alpha(0) mice (by 5.3 +/- 0.6%(NE), P< .001 vs WT) but preserved in TR alpha(Gs) arteries (by 17.2 +/- 1.1%(NE), not significant vs WT). Inhibition of either eNOS or PI3K reduced T-3 -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 T-3 -mediated vasodilation in rat mesenteric arteries (by 36.7 +/- 5.4%(NE) vs 3.5 +/- 6.2 degrees/0 NE ). In vivo, T-3 injection led to a rapid decrease of arterial BP in WT (by 13.9 +/- 1.9 mm Hg) and TR alpha(Gs) mice (by 12.4 +/- 1.9 mm Hg), but not in TR alpha(0) mice (by 4.1 +/- 1.9 mm Hg). Conclusion: These results demonstrate that T-3 acting through noncanonical TR alpha action affects cardiovascular physiology by inducing endothelium-dependent vasodilation within minutes via PI3K and eNOS activation.

Automated summary

The study aimed to characterize the role of 3,5,3'-triiodothyronine (T-3) and its receptors in regulating vasomotion. Results suggest that T-3 induces endothelium-dependent vasodilation within minutes through noncanonical TR alpha action, involving PI3K and eNOS activation.