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Role of phospholipase A 2 (PLA 2 ) and TRPV4 in endothelial Ca 2+ handling and endothelium‐dependent dilation
Author(s) -
Marrelli Sean Poul,
Bryan Robert M
Publication year - 2006
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.20.4.a296-d
Subject(s) - dilation (metric space) , endothelium , chemistry , trpv4 , microbiology and biotechnology , medicine , biochemistry , biology , mathematics , transient receptor potential channel , receptor , combinatorics
We recently demonstrated that endothelium‐derived hyperpolarizing factor (EDHF)‐mediated dilations of cerebral arteries could be blocked by inhibitors of phospholipase A 2 (PLA 2 ). The present studies extend this finding by elucidating the mechanism by which PLA 2 inhibition blocks dilation. We hypothesize that PLA 2 activation critically regulates Ca 2+ influx via TRPV4 channels in the initiation of EDHF‐dependent dilations. Male rat middle cerebral arteries (MCA) were mounted in an isolated vessel chamber. Arteries were cannulated (85 mm Hg pressure) and luminally perfused (100 ul/min). For measurement of endothelial [Ca 2+ ] i , the endothelium was selectively loaded with fura 2‐AM. Luminal delivery of UTP was used to elicit EDHF‐dependent dilations. L‐NAME and indomethacin were present throughout to block production of NO and prostaglandins, respectively. Luminal UTP (10 −7 to 10 −5 M) produced a dose‐dependent increase in endothelial Ca 2+ and maximal dilation of the artery at 10 ‐5 M UTP. Pre‐incubation with PACOCF3 (a PLA 2 inhibitor) abolished the endothelial Ca 2+ response and the dilation to UTP. Luminal administration of 4α‐PDD (an activator of TRPV4 channels) did not alter endothelial Ca 2+ or artery diameter. However, subsequent delivery of UTP produced significantly augmented Ca 2+ responses and a leftward shift of the diameter response. We conclude that liberation of AA through activation of PLA 2 modulates TRPV4 channel conductance of Ca 2+ . Thus, inhibition of EDHF‐mediated dilations by PLA 2 blockers may result from diminished endothelial Ca 2+ flux. Supported by AHA 0230353N, 0270110N and R01 NS46666