Brain-Selective Overexpression of Angiotensin (AT 1 ) Receptors Causes Enhanced Cardiovascular Sensitivity in Transgenic Mice

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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.