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Endothelial Pannexin1 can regulate cerebral myogenic tone development and severity of ischemic stroke
Author(s) -
Good Miranda Elizabeth,
Bacon Hannah M,
Eucker Stephanie A,
Lang Susan M,
Butcher Joshua T,
Johnson Tyler J,
Li Jun,
Zuo Zhiyi,
Isakson Brant E
Publication year - 2017
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.31.1_supplement.836.8
Subject(s) - myogenic contraction , vasoconstriction , cerebral circulation , medicine , endocrinology , carbenoxolone , vasodilation , anatomy , biology , gap junction , microbiology and biotechnology , smooth muscle , intracellular
Pannexin1 (Panx1) regulates adrenergic dependent vasoconstriction in peripheral arterioles; however, unlike peripheral arterioles, regulation of cerebral arteriole vasoconstriction is predominantly due to myogenic tone. Because ATP can elicit potent vasoconstriction of cerebral arterioles, we hypothesized that ATP release from Panx1 channels was involved in the development of myogenic tone of cerebral arterioles. Initially we found that myogenic tone in posterior cerebral arteries (PCAs) from wildtype mice was significantly inhibited when arterioles were treated with apyrase. Next we treated PCAs with pannexin pharmacological inhibitors (carbenoxolone, 10 Panx1, and spironolactone), which also significantly reduced the development of myogenic tone. Spironolactone, which we found does not inhibit Cx43 hemichannels, had no effect on myogenic tone development in peripheral arterioles (i.e, third order mesenteric arterioles). Next we used a genetic approach to pannexin inhibition and used either mice lacking Panx1 in smooth muscle cells (SMC; SMC‐Cre Panx1 fl/fl ) or endothelial cells (EC; EC‐Cre Panx1 fl/fl ). The myogenic tone was not altered in the SMC‐Cre Panx1 fl/fl mice, but was significantly reduced in the EC‐Cre Panx1 fl/fl mice. In line with the spironolactone data, myogenic tone development in peripheral arterioles of EC‐Cre Panx1 fl/fl mice was not different. Consistent with these data, we could detect no difference in blood pressure of EC‐Cre Panx1 fl/fl mice compared to control mice. Since myogenic tone regulates the cerebral blood flow and has been suggested to play a role in stroke outcome, we investigated the stroke infarct volume in both SMC‐Cre Panx1 fl/fl and EC‐Cre Panx1 fl/fl mice. Experimentally we used a 90 min intra‐luminal filament occlusion to induce ischemia of the middle cerebral artery followed by 24 hour reperfusion upon removal. We found that stroke infarct volume was significantly reduced in EC‐Cre Panx1 fl/fl mice, while SMC‐Cre Panx1 fl/fl mice showed no protection. Since EC‐Cre Panx1 fl/fl mice show reduced leukocyte rolling and adhesion following TNFα‐stimulation, we examined if these mice also demonstrate reduced infiltration of leukocytes. Preliminary data indicate that EC‐Cre Panx1 fl/fl mice have reduced overall number of leukocytes in the ischemic hemisphere compared to control mice. Our data demonstrate that Panx1 in endothelium may regulate ischemic stroke outcome, possibly through myogenic tone of cerebral arterioles and/or the extent of leukocyte infiltration. Support or Funding Information Funding: HL088554, HL120840, HL007284, HL131399.