Abstract 485: Potential Neuronal-Specific Influence on AT1a Receptor--Mediated Hyperplasia in the Ascending Aorta
Introduction and Objective: Angiotensin II (AngII) infusion stimulates AT1a receptors to promote medial thickening throughout the aorta. Medial thickening is due to hyperplasia in the ascending aorta and hypertrophy in the rest of the aorta. The cell type(s) expressing AT1a receptors that promote medial thickening have not been defined. We have previously demonstrated the surprising result that deletion of AT1a receptors in either endothelial or smooth muscle cells had no effect on medial thickening. Therefore, the purpose of this study was to determine the role of AT1a receptors in neuronal cells on AngII-induced aortic medial thickening.
Methods and Results: We generated male neuronal cell-specific AT1aR deficient mice by breeding AT1aR floxed mice with transgenic mice expressing Cre driven by enolase 2 promoter (AT1aR x Eno2 Cre +/0). Male non-transgenic littermates (AT1aR x Eno2 Cre 0/0) were used to compare AT1aR x Eno2 Cre +/0 mice. Mice were fed a normal laboratory diet and implanted with mini-osmotic pumps to infuse either saline or AngII (1,000 ng/kg/min) for 28 days. The expression of Cre had no effect on body weight or blood pressure. At termination, mice were perfusion-fixed at physiologic pressure and ascending and descending thoracic regions were sectioned serially. Aortic sections were stained with H&E and propodium iodide. The medial thickness (>5 per region) and nuclei counts (>2 per region) of each aortic tissue section was determined by image analysis. Cre expression under the control of Eno2 led to a significant reduction in medial thickness and number of nuclei in the ascending aorta (p<0.05). Conversely, there was no effect on medial thickening in the rest of the aorta. To determine specificity of Cre expression under control of the Eno2 promoter, Eno2 Cre+/0 mice were bred to ROSA26 mice which have repressed beta-galactosidase activity. In addition to the expected expression in neuronal cells, positive staining was also noted in the adventitia adjacent to the region of attenuated medial thickening.
Conclusion: AngII-induced ascending aortic hyperplasia was attenuated in mice in which AT1a receptors were deleted using Cre driven by the Eno2 promoter. However, the non-neuronal expression of Eno2 may be the basis for this effect.
- © 2012 by American Heart Association, Inc.