Endothelial Cell-Specific Aryl Hydrocarbon Receptor Knockout Mice Exhibit Hypotension Mediated, In Part, by an Attenuated Angiotensin II Responsiveness
Hypotension in aryl hydrocarbon receptor knockout mice (ahr−/−) is mediated, in part, by a reduced contribution of angiotensin (Ang) II to basal blood pressure (BP). Since AHR is highly expressed in endothelial cells (EC), we hypothesized that EC-specific ahr−/−(ECahr−/−) mice would exhibit a similar phenotype. We generated ECahr−/− mice by crossing AHR floxed mice (ahrfx/fx) to mice expressing Cre recombinase driven by an EC-specific promoter. BP was assessed by radiotelemetry prior to and following an acute injection of Ang II or chronic treatment with an angiotensin converting enzyme inhibitor (ACEi). ECahr−/− mice were hypotensive (ECahr+/+: 116.1 ± 1.4; ECahr−/−: 107.4 ± 2.0 mmHg, n = 11, p < 0.05) and exhibited significantly different responses to Ang II and ACEi. While Ang II increased BP in both genotypes, the increase was sustained in ECahr+/+, whereas the increase in ECahr−/− mice steadily declined. Area under the curve analysis showed that Ang II-induced increase in diastolic BP (DBP) over 30 min was significantly lower in ECahr−/− mice (ECahr+/+ 1297 ± 223 mmHg/30 min; ECahr−/−AUC: 504 ± 138 mmHg/30 min, p < 0.05). In contrast, while ACEi decreased BP in both genotypes, the subsequent rise in DBP after treatment was significantly delayed in the ECahr−/− mice. ECahr−/− mice also exhibited reduced vascular and adipose Ang II type 1 receptor (AT1R) expression, and reduced aortic Ang II-dependent vasoconstriction in the presence of vascular adipose. Taken together these data suggest that hypotension in ECahr−/− mice results from reduced vascular responsiveness to Ang II that is influenced by AT1R expression and adipose.
Agbor, L. N.,
Elased, K. M.,
& Walker, M. K.
(2011). Endothelial Cell-Specific Aryl Hydrocarbon Receptor Knockout Mice Exhibit Hypotension Mediated, In Part, by an Attenuated Angiotensin II Responsiveness. Biochemical Pharmacology, 82 (5), 514-523.