Objective: This study evaluated the consequences of thyroid hormone receptor-alpha (TR alpha) disruption on vascular reactivity. Methods: The activity of superior mesenteric arteries isolated from TR alpha knockout mice generated in the SV129 background (TR alpha(SV)-S-0/0) or in a pure C57BL/6 background (TR alpha(0/0)C57) was compared to that of their corresponding wild-type strains (SV129 or C57BL/6 mice). Results: The wildtype SV129 mice exhibited an impaired acetylcholine (Ach)-induced mesenteric artery relaxation compared to C57BL/6 mice, associated with greater responses to angiotensin II (AII) and phenylephrine (PE). The disruption of TRa decreased the vascular response to sodium nitroprusside and PE in both the SV129 and C57BL/6 genetic backgrounds. Responses to Ach and AII were also blunted, but only in TR alpha(0/0)C57 mice. The administration of 3,3'5-triiodo-L-thyronine sodium salt (T-3) elicited a vasodilatation in C57BL/6 mice even at the lowest concentration (10(-9) M); a maximal relaxation of more than 50% was observed with the concentrations between 10(-9) and 10(-8) M. However, the response to T-3 was nearly absent in TR alpha(0/0)C57 mice. Conclusion: TR alpha is essential for the control of vascular tone, particularly in thyroid hormone-mediated relaxation. The difference in response to Ach observed between the two wild-type mice should be taken into account for interpreting the vascular responses of genetically engineered mice.