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(Circulation Research. 2006;99:1125.)
© 2006 American Heart Association, Inc.

Integrative Physiology

Genetic Ablation of Angiotensinogen in the Subfornical Organ of the Brain Prevents the Central Angiotensinergic Pressor Response

Puspha Sinnayah, Eric Lazartigues, Koji Sakai, Ram V. Sharma, Curt D. Sigmund, Robin L. Davisson

From the Departments of Anatomy and Cell Biology (P.S., E.L., R.V.S, R.L.D.), Physiology and Biophysics (K.S., C.D.S.), Internal Medicine (K.S., C.D.S.), Radiation Oncology (Free Radical and Radiation Biology Program [R.L.D.]), and the Cardiovascular Center (R.V.S., C.D.S., R.L.D.), Roy J. and Lucille A. Carver College of Medicine, the University of Iowa, Iowa City.

Correspondence to Robin L. Davisson, PhD, Professor, Departments of Biomedical Sciences, College of Veterinary Medicine and Cell and Developmental Biology, Weill Cornell Medical College, Cornell University, Ithaca, New York 14853-6401. E-mail robin.davisson{at}cornell.edu

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 (hAGT^flox), 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.

Key Words: renin-angiotensin system • hypertension • Cre recombinase • transgenic mice • adenovirus

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