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Disruption of TRPV4 Ca 2+ signaling at myoendothelial projections (MEPs) contributes to endothelial dysfunction in Ang II hypertension
Author(s) -
Sonkusare Swapnil K,
Bonev Adrian D,
Dalsgaard Thomas,
Santana Luis F,
Kotlikoff Michael I,
Nelson Mark T
Publication year - 2013
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.27.1_supplement.876.7
Subject(s) - trpv4 , muscarinic acetylcholine receptor , endocrinology , medicine , endothelial dysfunction , vasodilation , chemistry , angiotensin ii , endothelium , mesenteric arteries , acetylcholine , receptor , transient receptor potential channel , artery
Endothelial cell (EC) dysfunction is a hallmark of hypertension, but the molecular mechanisms underlying this dysfunction remain unclear. We recently discovered elementary Ca 2+ signals (“sparklets”) through single TRPV4 channels at MEPs (Sonkusare et. al., Science, 2012). Activation of TRPV4 sparklets at MEPs by muscarinic agonists is responsible for 70% of EDH (endothelium derived hyperpolarization)‐dilation in 3 rd order mouse mesenteric arteries (MAs). Three weeks of angiotensin II (Ang II) infusion (1.4 mg/kg/day) leads to hypertension (HT) (systolic blood pressure, 178 mm Hg) and to a complete loss of the EDH‐mediated dilation without an effect on the NOS‐dependent component (20%). The maximal current density (i.e. channel number) of the ion channels (TRPV4, IK, SK, Kir) involved in the EDH dilation were unaffected in HT. Muscarinic receptor activation with carbachol increased TRPV4 sparklets at MEPs by 5‐fold in MAs from normotensive (NT) mice, but had no effect on TRPV4 sparklets from HT mice. IP3‐mediated increases in global Ca 2+ were unaffected. TRPV4‐activation of IK and SK currents in freshly isolated ECs was reduced by 50% in HT mice. Our results support the concept that endothelial dysfunction in this form of hypertension does not result from a loss of the signaling elements, but it reflects crippled local communication.