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Disruption of vasoconstrictor responses in isolated cerebral arteries following treatment with siRNA against TRPM4
Author(s) -
Gonzales Albert L,
Crnich Rachael,
Earley Scott
Publication year - 2008
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.22.1_supplement.1151.19
Subject(s) - depolarization , transient receptor potential channel , cerebral arteries , vasoconstriction , chemistry , agonist , myogenic contraction , medicine , membrane potential , vascular smooth muscle , endocrinology , receptor , biophysics , biology , biochemistry , smooth muscle
Membrane depolarization, Ca 2+ influx, and activation of the Ca 2+ ‐calmodulin pathway for smooth muscle contraction regulate arterial tone. The molecular mechanisms responsible for membrane depolarization in response to vasoconstrictor stimuli have not been fully characterized. We recently demonstrated that the melastatin transient receptor potential (TRP) channel TRPM4 is critical for membrane potential depolarization in response to increases in intraluminal pressure in cerebral arteries. In the current study, we further characterized the role of TRPM4 in intraluminal pressure‐ and agonist‐induced vasoconstriction using a newly developed RNA interference technique. Treatment of intact cerebral arteries with TRPM4 siRNA decreased mRNA expression by ~55% compared with controls. Using simultaneous video dimensional analysis and ratiometric Ca 2+ imaging , we found that arteries treated with TRPM4 siRNA (n=7) developed less myogenic tone and had lower smooth muscle intracellular Ca 2+ levels compared with controls (n=5). KCl (60 mM)‐induced constriction did not differ between groups. In addition, we found that TRPM4 siRNA‐treated arteries pressurized to 10 mmHg were less sensitive to the receptor‐dependent vasoconstrictor agonist uridine triphoshphate (UTP). These data suggest that TRPM4 plays a central role in regulating responses to vasoconstrictor stimuli in cerebral arteries. AHA0535226N