Faculty Collaboration Database

Brain-selective overexpression of angiotensin (AT1) receptors causes enhanced cardiovascular sensitivity in transgenic mice. Circ Res 2002 Mar 22;90(5):617-24

Date

03/23/2002

Pubmed ID

11909827

DOI

10.1161/01.res.0000012460.85923.f0

Scopus ID

2-s2.0-0037155772 (requires institutional sign-in at Scopus site)   69 Citations

Abstract

To examine the physiological importance of brain angiotensin II type 1 (AT1) receptors, we developed a novel transgenic mouse model with rat AT1a receptors targeted selectively to neurons of the central nervous system (CNS). A transgene consisting of 2.8 kb of the rat neuron-specific enolase (NSE) 5' flanking region fused to a cDNA encoding the full open-reading frame of the rat AT1a receptor was constructed and transgenic mice (NSE-AT1a) were generated. Two of six transgenic founder lines exhibited brain-selective expression of the transgene at either moderate or high levels. Immunohistochemistry revealed widespread distribution of AT1 receptors in neurons throughout the CNS. This neuron-targeted overexpression of AT1a receptors resulted in enhanced cardiovascular responsiveness to intracerebroventricular (ICV) angiotensin II (Ang II) injection but not to other central pressor agents, demonstrating functional overexpression of the transgene in NSE-AT1a mice. Interestingly, baseline blood pressure (BP) was not elevated in either transgenic line. However, blockade of central AT1 receptors with ICV losartan caused significant falls in basal BP in NSE-AT1a mice but had no effect in nontransgenic controls. These results suggest that whereas there is an enhanced contribution of central AT1 receptors to the maintenance of baseline BP in NSE-AT1a mice, particularly effective baroreflex buffering prevents hypertension in this model. Used both independently, and in conjunction with mice harboring gene-targeted deletions of AT1a receptors, this new model will permit quantitative and relevant investigations of the role of central AT1a receptors in cardiovascular homeostasis in health and disease.

Author List

Lazartigues E, Dunlay SM, Loihl AK, Sinnayah P, Lang JA, Espelund JJ, Sigmund CD, Davisson RL

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiotensin II
Animals
Antihypertensive Agents
Blood Pressure
Brain
Cardiovascular Physiological Phenomena
Immunohistochemistry
Injections, Intraventricular
Losartan
Mice
Mice, Transgenic
Models, Animal
Neurons
Organ Specificity
Phosphopyruvate Hydratase
Rats
Receptor, Angiotensin, Type 1
Receptors, Angiotensin
Recombinant Fusion Proteins
Transgenes