Abstract P055: Smooth Muscle Cell-specific Conditional Knockout Of Lysine (K)-specific Demethylase 6a Causes Endothelial Dysfunction, Increased Blood Pressure And Arterial Stiffness

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Arterial stiffening is the progressive loss of elasticity of the large vessels resulting from age. Increased arterial stiffening has been correlated with hypertension and other cardiovascular co-morbidities. KDM6A is a histone 3 lysine demethylase whose activity increases expression of target genes via removal of silencing methylation marks on lysine 27 of histone 3 (H3K27). The precise role of H3K27me3, or its absence in aortic vascular smooth muscle cells (VSMCs), remains to be investigated. The objectives of this study were to determine the effects of loss of KDM6A on arterial stiffness, blood pressure, and vascular cell function. We generated VSMC-specific Kdm6a knockout mice of C57BL/6 background and confirmed knockout by western blot. Knockout of Kdm6a resulted in increased resting systolic blood pressure and pulse wave velocity in male mice. Pulse wave velocity (PWV) is the gold-standard method for determination of arterial stiffness. PWVs of the knockout mice were significantly increased compared to controls four weeks after Kdm6a knockout (Controls 2.62 + 0.69 mm/ms; KO 3.13 + 0.30 mm/ms; P=0.0228). Systolic blood pressure was directly obtained for each mouse via carotid cannulation. The systolic blood pressures of knockout mice were significantly increased. Mesenteric arteries were isolated from three control and three Kdm6a knockout mice and mounted onto a wire myograph. Vessels were pre-constricted with norepinephrine and vasodilation was measured by treatment with increasing doses of acetylcholine and sodium nitroprusside to assess endothelial and VSMC function. Interestingly, despite Kdm6a knockout in VSMCs, vasodilation of VSMCs was not different between control and knockout arteries, but relaxation in response to acetylcholine, which stimulates the release of nitric oxide from endothelial cells, was decreased. This suggests endothelial dysfunction. These results indicate that loss of KDM6A in VSMCs leads to elevated systolic blood pressure and arterial stiffness.