3 years ago


Francois Alhenc-Gelas, Nathalie Caron, Catherine Chollet, Annette Hus-Citharel, Nadine Bouby, Sandrine Placier, Ronan Roussel, Christos Chatziantoniou
Angiotensin 1-converting enzyme (ACE) levels in man are under strong genetic influence. Genetic variation in ACE has been linked to risk for, and progression of, cardiovascular and renal diseases. Causality has been documented in genetically modified mice but mechanisms underlying causality are not completely elucidated. To further document the vascular and renal consequences of a moderate genetic increase in ACE synthesis, we studied genetically modified mice carrying three copies of the ACE gene (3-copy mice) and littermate wild type animals (2-copy mice). We investigated peripheral and renal vascular reactivity to angiotensin II and bradykinin in vivo by measuring blood pressure and renal blood flow after intravenous administration, and also reactivity of isolated glomerular arterioles by following intracellular calcium mobilisation. Carrying 3 copies of the ACE gene potentiated the systemic and renal vascular responses to angiotensin II over the whole range of peptide concentration tested. Consistently, response of isolated glomerular afferent arterioles to angiotensin II was enhanced in 3-copy mice. In these mice, signalling pathways triggered by endothelial activation by bradykinin or carbachol in glomerular arterioles were also altered. While the NOS-NO pathway was not functional in arterioles of 2-copy mice, in muscular efferent arterioles of 3-copy mice NOS3 gene expression was induced and NO mediated the effect of bradykinin or carbachol. These data document new and unexpected vascular consequences of a genetic increase in ACE synthesis. Enhanced vasoconstrictor effect of angiotensin II may contribute to the risk for cardiovascular and renal diseases linked to genetically high ACE level.

Publisher URL: http://doi.org/10.1152/ajpheart.00356.2017

DOI: 10.1152/ajpheart.00356.2017

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