Project Grant F30HL182271

BIASED ANGIOTENSIN RECEPTOR SIGNALING IN THE BRAINSTEM IN BLOOD PRESSURE REGULATION - PROJECT SUMMARY OVER A BILLION ADULTS WORLDWIDE MEET THE CLINICAL CRITERIA FOR HYPERTENSION, AND ELEVATED BLOOD PRESSURE IS RESPONSIBLE FOR OVER 7 MILLION DEATHS ANNUALLY. WHILE THE CURRENT TREATMENT MODALITY LARGELY EMPHASIZES SYSTEMIC INHIBITION OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM, AUTONOMIC DYSFUNCTION OFTEN PERSISTS EVEN AFTER NORMALIZING BLOOD PRESSURE. FURTHERMORE, THERE EXISTS COMPELLING EVIDENCE FOR A PRO-HYPERTENSIVE EFFECT DRIVEN BY TISSUE-SPECIFIC, INCLUDING BRAIN-SPECIFIC, RENIN-ANGIOTENSIN SYSTEMS. SUSTAINED ACTIVATION OF ANGIOTENSIN II TYPE 1 RECEPTORS (AT1RS) WITHIN THE BRAIN CAN RESULT IN PROFOUND AUTONOMIC IMBALANCE, FAVORING EXCESS SYMPATHETIC OUTFLOW, WHICH IN TURN, CONTRIBUTES TO THE PATHOGENESIS OF CARDIOVASCULAR DISEASE. THE AT1R IS A 7- TRANSMEMBRANE RECEPTOR THAT IS KNOWN TO SIGNAL THROUGH A G PROTEIN. LIKE MANY G PROTEIN-COUPLED RECEPTORS, THE AT1R CAN RECRUIT SIGNAL-TERMINATING B-ARRESTINS. USING EITHER A B-ARRESTIN-BIASED AGONIST OF THE AT1R OR A GLOBAL KNOCKOUT OF THE B-ARRESTIN2 GENE, WE HAVE PREVIOUSLY DEMONSTRATED THAT B-ARRESTIN2 EXERTS AN ANTI- HYPERTENSIVE EFFECT, BOTH GLOBALLY AND SPECIFICALLY WITHIN THE BRAIN. WHILE THESE STUDIES SHED LIGHT ON A PHYSIOLOGICALLY RELEVANT REGULATORY PATHWAY, QUESTIONS ABOUT THE ORIGIN OF ANGIOTENSIN II IN THE BRAIN REMAINED. THESE WERE DRIVEN CHIEFLY BY A LACK OF HIGH-QUALITY DATA DEMONSTRATING THE EXPRESSION OF RENIN, THE RATE LIMITING ENZYME OF THE RENIN-ANGIOTENSIN SYSTEM, WITHIN THE BRAIN. RECENTLY PUBLISHED DATA FROM OUR GROUP RESOLVED THIS DECADES LONG DEBATE BY IDENTIFYING A POPULATION OF CHOLINERGIC NEURONS WITHIN THE NUCLEUS AMBIGUOUS THAT EXPRESS RENIN. THE NUCLEUS AMBIGUOUS HOUSES PREGANGLIONIC VAGAL FIBERS THAT ARE WELL KNOWN FOR THEIR PARASYMPATHETIC CONTROL OF HEART RATE. HOWEVER, THE NUCLEUS AMBIGUUS HAS ALSO BEEN IMPLICATED IN BLOOD PRESSURE MODULATION. NEW DATA FROM OUR LAB HAS DEMONSTRATED THAT THE NUCLEUS AMBIGUUS EXPRESSES THE AT1R, AND THAT DIRECT STIMULATION OF THIS NUCLEUS WITH ANGIOTENSIN II RESULTS IN A PRESSOR RESPONSE. ADDITIONALLY, WE HAVE DEMONSTRATED THAT IN RESPONSE TO HYPERTENSION, THE EXPRESSION OF B-ARRESTINS WITHIN THE NUCLEUS AMBIGUUS IS REDUCED. HOWEVER, IT REMAINS UNKNOWN IF B-ARRESTIN SIGNALING SPECIFICALLY WITHIN THE NUCLEUS AMBIGUUS MEDIATES THE ANTI-HYPERTENSIVE EFFECT THAT WAS DEMONSTRATED IN PRIOR STUDIES. WE HYPOTHESIZE THAT B-ARRESTIN SIGNALING AT AT1RS IN CHOLINERGIC NEURONS OF THE NUCLEUS AMBIGUUS PLAYS A KEY ANTI-HYPERTENSIVE ROLE IN THE REGULATION OF BLOOD PRESSURE. HERE WE PROPOSE TWO SPECIFIC AIMS WHICH: 1) DEFINE THE ROLE OF B-ARRESTINS WITHIN CHOLINERGIC NEURONS OF THE NUCLEUS AMBIGUUS IN BLOOD PRESSURE REGULATION AND AUTONOMIC BALANCE, AND 2) SPECIFICALLY ASSESS THE ROLE OF B-ARRESTIN SIGNALING AT THE AT1R IN THESE NEURONS. USING STATE-OF-THE-ART GENETIC MODELS, WE WILL ENHANCE OUR UNDERSTANDING OF THE CARDIOVASCULAR ROLE OF THE B-ARRESTIN-MEDIATED AT1R SIGNALING CASCADE IN THESE NEURONS, POTENTIALLY DEFINING A NEW THERAPEUTIC TARGET FOR PATIENTS WITH RESISTANT HYPERTENSION.