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Knocking Out Endothelial TRPV4 Channels Enhances Vasoconstriction and Exacerbates Endothelial Dysfunction in Low‐Flow Vascular Injury
Author(s) -
McFarland Stuart Joseph,
Taylor Mark S.,
Weber David S.
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.581.9
Subject(s) - endothelial dysfunction , vasoconstriction , electrical impedance myography , medicine , myograph , vasodilation , phenylephrine , endocrinology , trpv4 , endothelium , chemistry , agonist , transient receptor potential channel , receptor , cardiology , blood pressure
Atherosclerosis remains a leading killer of men and women. It is associated with reduced blood flow, progressive endothelial dysfunction and vascular remodeling. Preventing pathologic endothelial changes is crucial for stopping the disease. Transient receptor potential cation channels (TRPV4) play a key role in endothelial responses to shear stress and local mediators by controlling dynamic endothelial Ca 2+ signals. In the current study, we assessed the specific impact of endothelial TRPV4 channels on carotid artery function in both wild type (WT) control and endothelial‐specific TRPV4 knockout transgenic mice (KO). Following tissue harvest, carotid arteries were cut into rings for Isometric force myography. Depolarization‐induced contractions (60 mM KCl) were larger in KO than WT arteries (1.14 ± 0.14 mN vs. 0.52 ± 0.08 mN, P<0.0005, N=6) and a similar trend was noted for contractions induced by the α1 adrenergic receptor agonist phenylephrine (0.68 ± 0.12 mN vs. 0.43 ± 0.08 mN, P<0.1, N=6). The calculated EC 50 indicated no significant difference (1.7×10 −7 vs 1.5×10 −7 M, n=6) in phenylephrine sensitivity. Net relaxation to acetylcholine was increased in KO vs. WT but EC 50 values were not significantly different (5.5×10 −7 vs 5.9×10 −7 , n=6). Using confocal imaging, endothelial Ca 2+ was evaluated in carotid artery segments that were cut open longitudinally. The dynamic Ca 2+ events that drive endothelium dependent vasorelaxation were altered in KO vs. WT arteries, exhibiting a lower frequency of these events but also events with larger mean amplitude and duration. A carotid artery partial ligation model was used to mimic the low flow predicted with atherosclerosis. Following 2 weeks of reduced flow, KO arteries demonstrated enhanced contractility and impaired ACh‐induced relaxation compared to similarly ligated WT arteries. Overall, our findings suggest that loss of endothelial TRPV4 channels inherently augments vasoconstriction and exacerbates endothelial dysfunction under conditions of chronic low flow. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .