Thyroid hormone affects both endothelial and vascular smooth muscle cells in rat arteries

Abstract

Hypothyroidism impairs endothelium-dependent dilatations, while hyperthyroidism augments the production of endothelial nitric oxide. Thus, experiments were designed to determine if thyroid hormone causes endothelium-dependent responses, or alleviates diabetic endothelial dysfunction. Isometric tension was measured in rings with or without endothelium of arteries from normal and diabetic Sprague-Dawley rats. Release of 6-keto prostaglandin F1α and thromboxane B2 were measured by enzyme linked immunosorbent assay and protein levels [endothelial nitric oxide synthase (eNOS), cyclooxygenases (COX)] by immunoblotting. Triiodothyronine (T3) caused concentration-dependent (3×10(-6)-3×10(-5)M) relaxations in mesenteric (pEC50, 4.96±0.19) and femoral (pEC50, 4.57±0.35) arteries without endothelium. In femoral arteries of rats with diabetes, 5-methylamino-2-[[(2S,3R,5R,8S,9S)-3,5,9-trimethyl-2-(1-oxo-(1H-pyrrol-2- -yl)propan-2-yl)-1,7-dioxaspiro-(5,5)undecan-8-yl]methyl]benzooxazole-4-carboxylic acid (A23187, 3×10(-7) to 10(-6)M) caused partly endothelium-dependent contractions. After chronic T3-treatment with (10μg/kg/day; four weeks), the contractions to A23187 of preparations with and without endothelium were comparable, the thromboxane B2-release was reduced (by 38.1±9.2%). The pEC50 of 9, 11-dideoxy-11α, 9α-epoxymethanoprostaglandin F2α (U46619, TP-receptor agonist) was increased in T3-treated diabetic rats compared with controls (8.53±0.06 vs 7.94±0.09). The protein expression of eNOS increased (by 228%) but that of COX-1 decreased (by 35%) after chronic T3 treatment. In human umbilical vein endothelial cells incubated for one week with T3 (10(-10)-10(-7)M) in the presence but not in the absence of interleukin-1β (1ng/ml), the expression of eNOS was increased compared to control. In conclusion, thyroid hormone acutely relaxes mesenteric and femoral vascular smooth muscle, but given chronically reduces the release of endothelium-derived vasoconstrictor prostanoids while enhancing the responsiveness of TP receptors of vascular smooth muscle.

Triiodothyronine Potentiates Vasorelaxation via PKG/VASP Signaling in Vascular Smooth Muscle Cells

“…Similarly, studies using isolated rat aortas have demonstrated that T3 induces endothelium-dependent vascular relaxation [20]. However, conflicting reports in the literature have demonstrated that T3 does not causes vasorelaxation per se , and that only high concentrations of T3 are able to causes relaxation in small vessels such as mesenteric and femoral arteries [10]. In this present study, we found that aortas acutely stimulated with T3 do not cause relaxation by itself but markedly potentiated vascular relaxation in response to vasoactive agents ACh and SNP.…”

“…More recently, others and our group have demonstrated that T3 also potentiates vascular relaxation via endothelium-independent mechanisms, suggesting that VSMC are a new target for T3-mediated vasodilation [10, 13]. The mechanisms underlying the rapid effects of T3 in mediating vascular relaxation remain poorly explored.…”

“…It is well known that T3 induces rapid vascular relaxation via both endothelium-dependent and endothelium-independent mechanisms [10-12]. Indeed, evidence has increasingly demonstrated that, besides EC, VSMC are an important target of T3 effects, which directly contribute to T3-induced vascular relaxation [13].…”

In silico modelling of prostacyclin and other lipid mediators to nuclear receptors reveal novel thyroid hormone receptor antagonist properties

“…Thyroid hormones have been shown to act directly on coronary artery smooth muscle cells [25] and rat mesenteric arteries [26] to induce vasodilation in a non-genomic manner, occurring within a few minutes of stimulation [17]. The mechanism and receptors responsible for T3 mediated dilation is emerging in the literature, with one recent study in TR␣ knockout mouse mesenteric arteries lacking the T3 vasodilatory effect.…”

Thyroid Hormone: A Therapy for Diabetic Vascular Complications?

“…We have demonstrated TH-induced rapid nitric oxide (NO) production in vascular smooth muscle (VSMC) via PI3K/Akt signaling, suggesting involvement of this pathway in TH mediated vascular relaxation [2]. Cai et al also observed that TH rapidly promotes vasorelaxation, with VSMC being a primary target of this hormone [3]. Inadequate TH production (hypothyroidism) is linked to impaired vascular reactivity and endothelial dysfunction [4].…”