Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension
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Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension. / Jobs, Alexander; Schmidt, Kjestine; Schmidt, Volker J; Lübkemeier, Indra; van Veen, Toon A B; Kurtz, Armin; Willecke, Klaus; de Wit, Cor.
I: Hypertension (Dallas, Tex. : 1979), Bind 60, Nr. 6, 12.2012, s. 1422-9.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Defective Cx40 maintains Cx37 expression but intact Cx40 is crucial for conducted dilations irrespective of hypertension
AU - Jobs, Alexander
AU - Schmidt, Kjestine
AU - Schmidt, Volker J
AU - Lübkemeier, Indra
AU - van Veen, Toon A B
AU - Kurtz, Armin
AU - Willecke, Klaus
AU - de Wit, Cor
PY - 2012/12
Y1 - 2012/12
N2 - The gap junction channel protein connexin40 (Cx40) is crucial in vascular and renal physiology, because Cx40-deficient mice exhibit impaired conduction of endothelium-dependent dilations and pronounced hypertension. The latter precludes mechanistic insights into the role of endothelial Cx40, because long-lasting hypertension itself may affect conduction and Cx expression. We aimed to identify endothelial Cx40 functions, their dependency on the conductive capability, and to separate these from hypertension-related alterations. We assessed conduction and Cx expression in mice with cell type-specific deletion of Cx40 and in mice expressing a defective Cx40 (Cx40A96S) identified in humans, which forms nonconducting gap junction channels. Confined arteriolar stimulation with acetylcholine or bradykinin elicited local dilations that conducted upstream without attenuation of the amplitude for distances up to 1.2-mm in controls with a floxed Cx40 gene (Cx40(fl/fl)). Conducted responses in hypertensive animals devoid of Cx40 in renin-producing cells were unaltered but remote dilations were reduced in normotensive animals deficient for Cx40 in endothelial cells (Cx40(fl/fl):Tie2-Cre). Surprisingly, Cx37 expression was undetectable by immunostaining in arteriolar endothelium only in Cx40(fl/fl):Tie2-Cre; however, transcriptional activity of Cx37 in the cremaster was comparable with Cx40(fl/fl) controls. Cx40A96S mice were hypertensive with preserved expression of Cx40 and Cx37. Nevertheless, conducted responses were blunted. We conclude that endothelial Cx40 is necessary to support conducted dilations initiated by endothelial agonists and to locate Cx37 into the plasma membrane. These functions are unaltered by long-lasting hypertension. In the presence of a nonconducting Cx40, Cx37 is present but cannot support the conduction highlighting the importance of endothelial Cx40.
AB - The gap junction channel protein connexin40 (Cx40) is crucial in vascular and renal physiology, because Cx40-deficient mice exhibit impaired conduction of endothelium-dependent dilations and pronounced hypertension. The latter precludes mechanistic insights into the role of endothelial Cx40, because long-lasting hypertension itself may affect conduction and Cx expression. We aimed to identify endothelial Cx40 functions, their dependency on the conductive capability, and to separate these from hypertension-related alterations. We assessed conduction and Cx expression in mice with cell type-specific deletion of Cx40 and in mice expressing a defective Cx40 (Cx40A96S) identified in humans, which forms nonconducting gap junction channels. Confined arteriolar stimulation with acetylcholine or bradykinin elicited local dilations that conducted upstream without attenuation of the amplitude for distances up to 1.2-mm in controls with a floxed Cx40 gene (Cx40(fl/fl)). Conducted responses in hypertensive animals devoid of Cx40 in renin-producing cells were unaltered but remote dilations were reduced in normotensive animals deficient for Cx40 in endothelial cells (Cx40(fl/fl):Tie2-Cre). Surprisingly, Cx37 expression was undetectable by immunostaining in arteriolar endothelium only in Cx40(fl/fl):Tie2-Cre; however, transcriptional activity of Cx37 in the cremaster was comparable with Cx40(fl/fl) controls. Cx40A96S mice were hypertensive with preserved expression of Cx40 and Cx37. Nevertheless, conducted responses were blunted. We conclude that endothelial Cx40 is necessary to support conducted dilations initiated by endothelial agonists and to locate Cx37 into the plasma membrane. These functions are unaltered by long-lasting hypertension. In the presence of a nonconducting Cx40, Cx37 is present but cannot support the conduction highlighting the importance of endothelial Cx40.
KW - Acetylcholine/pharmacology
KW - Animals
KW - Blood Pressure/physiology
KW - Connexins/genetics
KW - Endothelial Cells/drug effects
KW - Endothelium, Vascular/drug effects
KW - Gap Junctions/drug effects
KW - Heart Rate/physiology
KW - Hypertension/genetics
KW - Mice
KW - Mice, Transgenic
KW - Vasodilation/drug effects
U2 - 10.1161/HYPERTENSIONAHA.112.201194
DO - 10.1161/HYPERTENSIONAHA.112.201194
M3 - Journal article
C2 - 23090768
VL - 60
SP - 1422
EP - 1429
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 6
ER -
ID: 329568827