Project Grant F32HL188939

ANGIOTENSIN II-MEDIATED NEUROVASCULAR DYSFUNCTION IN THE NUCLEUS OF THE SOLITARY TRACT DURING HEART FAILURE - PROJECT SUMMARY HEART FAILURE (HF) IS A MAJOR PUBLIC HEALTH BURDEN, AND BLUNTED BAROREFLEX (BR) FUNCTION IS A DEFINING FEATURE OF THIS DISEASE. OVERACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM (RAS) IS A KEY CONTRIBUTOR TO THE PATHOPHYSIOLOGY OF HF, AND THERAPIES TARGETING THE RAS, SUCH AS LOSARTAN, IMPROVE AUTONOMIC BALANCE AND OUTCOMES IN HF. THE NUCLEUS OF THE SOLITARY TRACT (NTS) INTEGRATES BARORECEPTOR INPUTS TO MAINTAIN CARDIOVASCULAR HOMEOSTASIS AND SERVES AS A CENTRAL TARGET OF RAS-DRIVEN BARORECEPTOR DYSFUNCTION. YET, THE MECHANISMS THAT LINK NEURONAL ACTIVITY IN THE NTS TO LOCAL VASCULAR RESPONSES, AN ESSENTIAL PROCESS FOR MAINTAINING NORMAL NEURONAL SIGNALING AND FUNCTIONAL INTEGRITY, REMAIN POORLY UNDERSTOOD. NEUROVASCULAR COUPLING (NVC), THE PROCESS MATCHING NEURONAL ACTIVITY WITH LOCAL CEREBRAL BLOOD FLOW (CBF), IS IMPAIRED IN THE CORTEX DURING HF AND CONTRIBUTES TO COGNITIVE DECLINE. WHETHER SIMILAR NVC DEFICITS OCCUR IN THE NTS AND CONTRIBUTE TO BLUNTED BR FUNCTION IS UNKNOWN. ADDRESSING THIS GAP COULD REVEAL NEW THERAPEUTIC STRATEGIES TO RESTORE AUTONOMIC REGULATION IN HF. TO TEST THIS, I DEVELOPED A NOVEL IN VIVO RAT MODEL THAT ENABLES HIGH-RESOLUTION TWO-PHOTON IMAGING OF NVC WITHIN THE NTS DURING BR ACTIVATION. USING BARORECEPTOR LOADING (IV PHENYLEPHRINE, TO INCREASE BLOOD PRESSURE) AND UNLOADING (IV SODIUM NITROPRUSSIDE TO REDUCE BLOOD PRESSURE), I CAN DIRECTLY MEASURE NTS MICROVASCULAR RESPONSES, INCLUDING CHANGES IN ARTERIOLE DIAMETER AND BLOOD FLOW. MY PRELIMINARY DATA DEMONSTRATE FOR THE FIRST TIME: (1) SUCCESSFUL IN VIVO IMAGING OF DISTINCT NTS VASCULAR COMPARTMENTS AND DYNAMICS, (2) ROBUST BR- EVOKED NVC RESPONSES, AND (3) BLUNTED BR-EVOKED FUNCTIONAL HYPEREMIA IN A MYOCARDIAL INFARCTION MODEL OF HF. THE PROPOSED PROJECT WILL AIM TO (1) DEFINE THE MECHANISMS MEDIATING BR-EVOKED NVC IN THE NTS, TESTING THE ROLE OF NITRIC OXIDE AS A KEY UNDERLYING SIGNAL; AND (2) DETERMINE WHETHER RAS OVERACTIVATION DRIVES IMPAIRED NVC IN HF, AND WHETHER ITS INHIBITION RESTORES NORMAL VASCULAR RESPONSES. BY ESTABLISHING NVC AS A NOVEL MECHANISM CONTRIBUTING TO AUTONOMIC IMBALANCE IN HF, THIS RESEARCH IDENTIFIES NEW THERAPEUTIC TARGETS TO IMPROVE BR REGULATION. THESE STUDIES DIRECTLY ADVANCE FUNDAMENTAL KNOWLEDGE OF NEURAL CONTROL OF CARDIOVASCULAR HEALTH AND AIM TO IMPROVE OUTCOMES IN PATIENTS WITH HF.