Genetic ablation of angiotensinogen in the subfornical organ of the brain prevents the central angiotensinergic pressor response

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Sinnayah, Puspha, Lazartigues, E, Sakai, K, Sharma, R, Sigmund, C and Davisson, R (2006) Genetic ablation of angiotensinogen in the subfornical organ of the brain prevents the central angiotensinergic pressor response. Circulation Research, 99 (10). pp. 1125-1131. ISSN 0009-7330

Abstract

The subfornical organ (SFO) of the brain has long been considered a critical integrating center for the cardiovascular actions of the renin-angiotensin system (RAS). Early reports of angiotensin II (Ang II) immunoreactivity in the SFO and its neural projections to downstream cardiovascular nuclei raised the possibility that Ang II is produced locally and functions as a putative neurotransmitter in these circuits. However, evidence of functionally significant de novo synthesis of Ang II in the SFO has been lacking. Here, implementing spatiotemporally restricted gene ablation by way of the Cre recombinase/loxP system, we provide the first direct evidence that the local RAS in the SFO has a critical role in blood pressure regulation. Using a transgenic mouse harboring an angiotensinogen (AGT) gene modified for Cre-mediated deletion (hAGTflox), in combination with gene transfer of an adenovirus encoding Cre targeted to the SFO, we show that deletion of the Ang II substrate in this brain region nearly abolishes the pressor and bradycardic effects of renin infused in the CNS. Immunohistochemical analyses verified intense and restricted expression of Cre in the SFO, which paralleled the decrease in AGT expression selectively in this site. Further physiological studies confirmed the integrity of central angiotensinergic and nonangiotensinergic cardiovascular response systems in the Cre-treated mice. In addition to establishing that AGT expression in the SFO and its local conversion to Ang II has a profound effect on blood pressure, this study provides proof-of-principle of the utility of this approach for dissecting the brain RAS and other complex systems in CNS cardiovascular circuits.

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Additional Information

Online ISSN: 1524-4571

Item type Article
URI https://vuir.vu.edu.au/id/eprint/8062
DOI https://doi.org/10.1161/01.RES.0000250259.66683.f5
Official URL http://dx.doi.org/10.1161/01.RES.0000250259.66683....
Subjects Historical > FOR Classification > 1101 Medical Biochemistry and Metabolomics
Historical > FOR Classification > 1102 Cardiorespiratory Medicine and Haematology
Keywords ResPubID22108. renin-angiotensin system, hypertension, Cre recombinase, transgenic mice, adenovirus, genetics, DNA, subfornical organ, brain, cardiovascular, blood pressure regulation, peptides, mice
Citations in Scopus 37 - View on Scopus
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