The brain plays a critical role in the maintenance of cardiovascular homeostasis. It receives, processes, and integrates neurohumoral signals that reflect the blood pressure and body fluid status of the organism. It then engages appropriate autonomic endocrine and behavior effector systems to optimize and restore balance. Disordered regulation of cardiovascular homeostasis is associated with diseases such as hypertension. Although multiple lines of evidence suggest that the brain-renin angiotensin system figures prominently in these complex processes in both health and disease, a lack of understanding of fundamental aspects of this system has prevented from determining its precise role. Uncertainty about the organization of the brain RAS at the cellular level is the central issue. Evidence suggests that the only known precursor of Ang II, angiotensinogen (AGT) is localized to both astrocytes and neurons in the brain. Recently the PI has utilized a transgenic mouse model with easily detectable AGT levels to map brain AGT expression in situ. The PI found that AGT is localized to astrocytes in widespread regions but its expression in neurons is highly restricted to two neural axes, the forebrain SFO-hypothalamic-hypofacial axis and the brainstem parabrachial-amygdala circuit. Both are known to be important in cardiovascular homeostasis. The goal of this proposal is to determine the relative functional significance of neuronal and astrocytic AGT in cardiovascular regulation in vivo. The PI will utilize Cre-loxP technology, a highly selective gene ablation strategy to target deletion of AGT transgene separately in each of the two neural circuits and in astrocytes. The effect of permanent ablation of AGT in each of the brain angiotensinergic systems on long term cardiovascular regulation in conscious rat will be examined. The PI will also determine whether changes in cardiovascular function resulting from AGT deletion correlate with a loss of Ang II immunoreactivity in nerve cells/fibers. Finally, the PI proposes to determine the role of each of these brain angiotensinergic systems in a genetic model of RAS-dependent hypertension and in non-hypertensive animals. The PI believes that these studies will address the long-sought question of neuronal versus astroglial AGT in central RAS function and as such provide fundamental knowledge about the mechanisms of normal and pathological regulation of cardiovascular homeostasis.
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