Premium
Loss of local Ca 2+ signaling networks in the endothelium in diet induced obesity
Author(s) -
Hong Kwangseok,
Cope Eric L,
Marziano Corina,
Sonkusare Swapnil K
Publication year - 2016
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.30.1_supplement.lb607
Subject(s) - transient receptor potential channel , trpv4 , vasodilation , agonist , endocrinology , medicine , chemistry , endothelium , receptor , electrical impedance myography , mesenteric arteries , biophysics , biology , artery
Endothelial cells (ECs) play a crucial role in regulating vascular function. Weakening of local Ca 2+ signaling networks in the ECs leads to the loss of endothelial vasodilation in hypertension (Sonkusare et al., Science Signaling, 2014). There is increasing evidence that obesity is also associated with a loss of endothelial function. The objective of this study was to determine the impact of diet‐induced obesity (DIO) on the local Ca 2+ signaling networks that regulate endothelial vasodilation. We recently showed that elementary Ca 2+ influx events through endothelial TRPV4 (transient receptor potential vanilloid 4) channels (TRPV4 Ca 2+ sparklets) dilate mesenteric arteries (MAs) via Ca 2+ ‐sensitive, intermediate conductance K + (IK) channels (Sonkusare et al., Science, 2012). Moreover, muscarinic receptor agonist carbachol (CCh) dilates MAs via activation of TRPV4 sparklets at myoendothelial projections (MEPs), an interaction that requires MEP‐localized A kinase anchoring protein 150 (AKAP150). Diameter studies were performed in 3 rd order mouse MAs constricted by intravascular pressure (80 mm Hg) and Ca 2+ events were recorded in the slit‐open, pinned down MAs using a spinning disk confocal imaging system. After 8–10 weeks of high‐fat diet feeding, the vasodilations to CCh (0.3–10 μM) and GSK1016790A (TRPV4 channel agonist, 3–30 nM) were attenuated in the DIO mice. The activity of TRPV4 sparklets, recorded as the fluorescence integral of all the sparklet sites per field of view (~14 ECs), was 4‐fold lower in the DIO mice compared to the mice fed with a normal diet. Whereas 90% of MEPs showed identifiable AKAP150 staining in the control mice, only 32% MEPs showed AKAP150 staining in the DIO mice. These results support the concept that a loss of AKAP150 from the MEPs and resulting TRPV4 channel dysfunction may be responsible for impaired endothelial vasodilation in the DIO mice. Support or Funding Information Funded by NIH award HL121484 to SKS.