Noncanonical Thyroid Hormone Receptor α Action Mediates Arterial Vasodilation

Abstract

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.

Thyroxine Induces Acute Relaxation of Rat Skeletal Muscle Arteries via Integrin αvβ3, ERK1/2 and Integrin-Linked Kinase

“…The T3-induced effect was endothelium-dependent, similar to observed in the aorta (Lozano-Cuenca et al, 2016) and skeletal muscle arterioles (Park et al, 1997). The acute action of T3 in endothelial cells is mediated by the cytoplasmic TRα1 receptor and PI3K/Akt signaling cascade with a subsequent eNOS activation and NO production (Colantuoni et al, 2005;Hiroi et al, 2006;Aoki et al, 2015;Lozano-Cuenca et al, 2016;Geist et al, 2021). Presumably, similar mechanisms are involved in the observed endotheliumdependent T3-induced relaxation of rat sural arteries.…”

“…Non-genomic effects of TH may be mediated by various receptors including cytoplasmic TRα and TRβ, truncated isoforms of TRα and integrin αvβ3 (Plateroti et al, 2001;Hiroi et al, 2006;Kalyanaraman et al, 2014;Selivanova and Tarasova, 2020;Davis et al, 2021;Geist et al, 2021). TH binding to these receptors could initiate different signaling pathways involving Src-kinase, phosphoinositide-3 kinase (PI3K)/Akt cascade, extracellular signal-regulated protein kinases (ERK1/2) (Cao et al, 2005;Moeller et al, 2005;Lin et al, 2009).…”

Acute Effects of Liothyronine Administration on Cardiovascular System and Energy Metabolism in Healthy Volunteers

“…Studies performed in ex vivo models of vasculature contractility are conflicting: Gachkar and colleagues demonstrated a rapid response to physiologic concentrations of T3, and a decreased response to both hyper-and hypothyroid concentrations, not mediated by AKT, ERK or AMPK (21). More recently, other authors demonstrated an increase in vasodilation following exposure to T3, mediated by PI3K pathway and thyroid hormone receptor alpha (22). Experiments conducted in an animal model of hypothyroidism indicate that exposure to high dose LT3 generates a measurable transcriptional effect within 30' reaching a maximum effect after 6 hours (23).…”

Region-specific effects of antenatal/early postnatal hypothyroidism on endothelial NO-pathway activity in systemic circulation

“…Thyroid hormones are established regulators of endothelial NO-pathway activity ( McAllister et al, 2005 ; Samuel et al, 2017 ; Selivanova and Tarasova, 2021 ). Endothelial NO-synthase (eNOS) expression and activity are controlled by thyroid hormone receptor α (TRα) ( Hiroi et al, 2006 ; Suarez et al, 2014 ; Geist et al, 2021 ) for which T3 has a greater affinity than T4 ( Schroeder et al, 2014 ). Thuswise, T3 may be considered as a more active regulator of arterial vasomotor responses mediated by eNOS.…”