BACKGROUND: Hypothyroidism impairs cardiovascular health and contributes to endothelial dysfunction with reduced vasodilation. How 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). Here we aimed to characterize the T3 action underlying the mechanism of arterial vasodilation and blood pressure regulation. METHODS: Mesenteric arteries were isolated from male rats, wildtype (WT) mice, TRα knockout (TRα 0) mice and from knock-in 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 pre-constricted 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 percent vasodilation after maximal pre-constriction with norepinephrine (% NE). Isolated vessels were treated with T3 (1x10 -15 to 1x10 -5 mol/L) alone and in combination with the endothelial NO-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 blood pressure 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<0.0001 vs. WT) but preserved in TRαGS arteries (by 17.2±1.1% NE, n.s. 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 blood pressure in WT (by 13.9±1.9 mmHg) and TRαGS mice (by 12.4±1.9 mmHg), but not in TRα0 mice (by 4.1±1.9 mmHg). CONCLUSIONS: These results demonstrate that T3 acting through noncanonical TRa action impacts cardiovascular physiology by inducing endothelium-dependent vasodilation within minutes via PI3K and eNOS activation.
BACKGROUND:Hypothyroidism impairs cardiovascular health and contributes to endothelial dysfunction with reduced vasodilation. How 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). Here we aimed to characterize the T3 action underlying the mechanism of arterial vasodilation and blood pressure regulation. METHODS: Mesenteric arteries were isolated from male rats, wildtype (WT) mice, TRα knockout (TRα 0) mice and from knock-in 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 pre-constricted 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 percent vasodilation after maximal pre-constriction with norepinephrine (% NE). Isolated vessels were treated with T3 (1x10 -15 to 1x10 -5 mol/L) alone and in combination with the endothelial NO-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 blood pressure 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<0.0001 vs. WT) but preserved in TRαGS arteries (by 17.2±1.1% NE, n.s. 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 blood pressure in WT (by 13.9±1.9 mmHg) and TRαGS mice (by 12.4±1.9 mmHg), but not in TRα0 mice (by 4.1±1.9 mmHg). CONCLUSIONS: These results demonstrate that T3 acting through noncanonical TRa action impacts cardiovascular physiology by inducing endothelium-dependent vasodilation within minutes via PI3K and eNOS activation.
Authors: Dina K Gaynullina; Svetlana I Sofronova; Ekaterina K Selivanova; Anastasia A Shvetsova; Anna A Borzykh; Olga S Tarasova Journal: Curr Res Physiol Date: 2021-12-14
Authors: Shanshan Chen; George F Wohlford; Alessandra Vecchie'; Salvatore Carbone; Sahzene Yavuz; Benjamin Van Tassell; Antonio Abbate; Francesco S Celi Journal: Front Endocrinol (Lausanne) Date: 2022-02-28 Impact factor: 5.555