Brain-selective overexpression of angiotensin (AT₁) receptors causes enhanced cardiovascular sensitivity in transgenic mice

To examine the physiological importance of brain angiotensin II type 1 (AT₁) receptors, we developed a novel transgenic mouse model with rat AT_1a 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 AT_1a receptor was constructed and transgenic mice (NSE-AT_1a) 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 AT_1a 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-AT_1a 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-AT_1a 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-AT_1a mice, particularly effective baroreflex buffering prevents hypertension in this model. Used both independently, and in conjunction with mice harboring gene-targeted deletions of AT_1a receptors, this new model will permit quantitative and relevant investigations of the role of central AT_1a receptors in cardiovascular homeostasis in health and disease.