Date of Award

Spring 4-21-2025

Embargo Period

4-22-2030

Document Type

Dissertation - MUSC Only

Degree Name

Doctor of Philosophy (PhD)

Department

Molecular and Cellular Biology and Pathobiology

College

College of Graduate Studies

First Advisor

Takako Makita

Abstract

The sympathetic nervous system (SNS) regulates heart rate and contractility in response to a variety of physical and emotional stresses. Proper formation and maintenance of sympathetic synapses are critical for SNS function, yet the underlying molecular mechanisms remain poorly understood. This dissertation investigates the role of Endothelin Receptor B (Ednrb) in the establishment and preservation of sympathetic synapses, as well as the structural and functional consequences of reduced sympathetic input. We investigate the role of Ednrb using two sympathetic neuron-specific Ednrb knockout mouse models: Th-cre/Ednrb, in which Ednrb is deleted embryonically, and THCreER/Ednrb where deletion is induced postnatally, at 3 weeks of age. We used fluorescence-based markers to visualize functional synapses of the heart and kidneys. Cardiac function was evaluated through electrocardiography, IonOptix imaging of isolated primary cardiomyocytes, and western blot analysis of proteins involved in contractility and calcium handling. Our results indicate that Ednrb deletion in sympathetic neurons significantly reduces functional sympathetic nerves in the heart, regardless of whether Ednrb loss occurs embryonically or postnatally. However, we find divergent outcomes in intrinsic cardiomyocyte function depending on when synaptic transmission at neuroeffector junction is impaired. Loss of communication between sympathetic synapses and developing cardiomyocytes resulted in a failure of cardiomyocyte to acquire normal contractile function, and ultimately led to ventricular arrhythmias. In contrast, elimination of sympathetic synaptic transmission to mature cardiomyocytes led to elevation of beta-adrenergic receptor expression and thereby beta-adrenergic hypersensitivity. These cardiomyocyte-specific responses to loss of local sympathetic neurotransmission are not compensated by systemic catecholamines and are relevant to clinical interventions for heart diseases, such as beta blocker therapy and surgical sympathectomy. Furthermore, our findings reveal that the synaptic phenotype associated with the loss of Ednrb from cardiac sympathetic nerves is not mirrored in the mature renal sympathetic nerves. These results suggest that the mechanisms of synaptic maintenance may vary between organ systems. While further research is essential to elucidate the precise mechanisms underlying Ednrb function in this context, the work presented in this dissertation overall enhances our understanding of the SNS’s role in cardiac physiology and the factors that influence sympathetic synapse formation and maintenance.

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Copyright is held by the author. All rights reserved.

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Available for download on Monday, April 22, 2030

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