JS-ECCR/HBPRCA-4: NEURAL CONTROL OF CARDIOVASCULAR FUNCTION AND ERYTHROPOIESIS BY THE BRAIN RAS

Abstract

The renin-angiotensin system (RAS) strongly modulates not only cardiovascular homeostasis but also other non-cardiovascular physiological processes like erythropoiesis. The production of the peptide hormone angiotensin II (Ang II) in the circulatory system constitutes the main source of the RAS activity. However, Ang II has also been recognized to be generated locally by various tissues, because RAS components are either locally expressed and/or imported from the circulation. Contrary to peripheral organs, the blood-brain-barrier limits the traffic of all circulating RAS proteins into the brain, thus, brain Ang II formation relies exclusively on locally expressed RAS precursor and enzymes. Several brain cardiovascular centers contain neuronal populations responsive to Ang II that take part in sympathetic nerve outflow, vasopressin secretion, thirst and salt appetite. Angiotensinogen (Agt), the RAS precursor, is mostly produced by astrocytes in the brain. To investigate the role of the brain RAS in cardiovascular control and erythropoiesis, two transgenic rodent models with astrocyte-specific Agt gain- and loss-of-function were phenotyped. In both models, astrocyte-specific transgene expression was delivered using the human GFAP promoter. The gain-of-function model is a transgenic mouse overexpressing rat Agt, and the loss-of-function model is a rat expressing an antisense RNA against the endogenous Agt mRNA. The transgenic mouse line overexpresses the rat Agt mRNA distributed across the brain, including areas containing cardiovascular centers. Overexpression of Agt increased brain Ang II formation but reduced the peripheral Ang II levels. Rats expressing the antisense RNA exhibited a brain-specific decrease of Agt protein by ∼90%. The cardiovascular phenotyping of the two lines demonstrated opposing effects for the brain RAS. Increased brain RAS reactivity was associated with high BP, vascular sympathetic tone and vasopressin secretion, and downregulation of the brain RAS reduced BP and vasopressin secretion. Similarly, the brain RAS modulated erythropoiesis in contrary directions because capillary hematocrit experiments revealed that overproduction of Ang II in the brain correlates with increased erythropoiesis while reduced Ang II production with moderated erythropoiesis. These findings were further validated using detailed blood cell counting with an automated hematology analyzer. Submitting the transgenic mice with increased brain Ang II and respective controls to peripheral sympathectomy with 6-hydroxydopamine revealed that brain Ang II via sympathetic nerve activity increases erythropoiesis in transgenic mice. Altogether, these models confirmed the functionality of the brain RAS, and that baseline BP and erythropoiesis depends on its integrity and reactivity.