TY - JOUR T1 - Triiodothyronine reduces vascular dysfunction associated with hypertension by attenuating PKG/VASP signaling. JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.119.260471 SP - jpet.119.260471 AU - Maria Alicia Carrillo-Sepulveda AU - Anjali Panackal AU - Renjith Maracheril AU - Nicole Maddie AU - Mitul N Patel AU - Kaie Ojamaa AU - Olga V Savinova AU - A. Martin Gerdes Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/07/12/jpet.119.260471.abstract N2 - 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. ER -