title: Endothelial cell-specific aryl hydrocarbon receptor knockout mice exhibit hypotension mediated, in part, by an attenuated angiotensin II responsiveness.
abstract: 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 (ahr(fx/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.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, University of New Mexico, Health Sciences Center, Albuquerque, NM, USA.
authors.forename: Larry N
authors.initials: LN
authors.lastname: Agbor
authors.forename: Khalid M
authors.initials: KM
authors.lastname: Elased
authors.forename: Mary K
authors.initials: MK
authors.lastname: Walker
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D001794:Blood Pressure / Q000187:drug effects; D042783:Endothelial Cells / Q000502:physiology*; D005260:Female; D006339:Heart Rate; D007022:Hypotension / Q000209:etiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009929:Organ Size; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D012084:Renin-Angiotensin System / Q000502:physiology; D013564:Sympathetic Nervous System / Q000502:physiology
chemical_list: D000804:Angiotensin II; D051792:Basic Helix-Loop-Helix Proteins; D019001:Nitric Oxide Synthase; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D018336:Receptors, Aryl Hydrocarbon; C484722:Ahr protein, mouse