Triiodothyronine reduces vascular dysfunction associated with hypertension by attenuating PKG/VASP signaling.

Vascular dysfunction associated with hypertension comprises hypercontractility and impaired vasodilation. We have previously demonstrated that triiodothyronine (T3), the active form of thyroid hormone, has vasodilatory effects acting through rapid on-set mechanisms. In the present study, we examined whether T3 mitigates vascular dysfunction associated with hypertension. To test direct effects of T3 in hypertensive vessels, aortas from female Dahl salt-sensitive (Dahl SS) rats, fed a high-salt diet (8% NaCl, HS Group) and their age-matched controls, fed a standard low salt diet (0.3% NaCl, LS Group) for 16 weeks, were isolated and utilized in ex vivo vascular reactivity studies. We confirmed that the HS Group exhibited a higher systolic blood pressure in comparison to the control LS Group, and displayed aortic remodeling. Aortas from both groups were pre-treated with T3 (0.1 μM) for 30 minutes at 37°C in a 5% CO2 incubator prior to functional vascular studies. T3 treatment significantly attenuated hypercontractility and improved impaired endothelium-dependent vasodilation in aortas from the HS group. These vascular improvements in response to T3 were accompanied by increased phosphorylation of vasodilator-stimulated phosphoprotein (VASP) at serine 239, a vasodilatory factor of the cGMP-dependent protein kinase (PKG)/VASP signaling pathway in vascular smooth muscle cells (VSMC). Moreover, increased production of reactive oxygen species (ROS) in aortas from the HS group were significantly reduced by T3, suggesting a potential anti-oxidant effect of T3 in the vasculature. These results demonstrate that T3 can mitigate hypertension-related vascular dysfunction, through the VASP signaling pathway and by reducing vascular ROS production. SIGNIFICANCE STATEMENT This study demonstrates that T3 directly acts on vascular tone and has a beneficial effect in hypertension-induced vascular dysfunction. T3 augmented vasodilation and diminished vasoconstriction in blood vessels from hypertensive rats in association with activation of the PKG/VASP signaling pathway that activates vascular relaxation, and exerted an anti-oxidant effect. Collectively, these results show that T3 is a potential vaso-protective agent with rapid action on hypertension-related vascular dysfunction.