All ETDs from UAB

Advisory Committee Chair

Daniel A Gorelick

Advisory Committee Members

Kai Jiao

Michael A Miller

John Parant

Qin Wang

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Estrogens regulate cell signaling and gene expression by binding to nuclear estrogen receptors (ERs) alpha and beta (ERα, ERβ), ligand-dependent transcription factors. Estrogens also activate the G protein-coupled estrogen receptor (GPER), however the function of GPER in vivo is less well understood. In the cardiovascular system, estrogens regulate vessel pressure and exert cardioprotective effects on the vasculature. However, whether estrogens act directly to modulate heart function, and the mechanism by which this occurs is not well understood. Therefore, the overall goals of this dissertation were to (1) determine if estrogen receptor ligands modulate heart rate and to (2) determine the receptor, (3) tissue type and (4) mechanism by which estrogen ligands modulate heart rate. Using pharmacological and genetic loss-of-function experiments, we find that (1) estrogens, not other steroid hormones, consistently and reproducibly modulate heart rate. Acute exposure to estrogens increased heart rate in wildtype and in ERα and ERβ mutant embryos but not in GPER mutants. GPER mutant embryos exhibited reduced basal heart rate, while heart rate was normal in ERα and ERβ mutants. These data suggest that (2) estrogen receptor ligands act via GPER, but not nuclear ERs, to modulate heart rate. Using whole-mount colorimetric in situ hybridization, we (3) detected gper transcript in discrete regions of the brain but not in the heart, suggesting that GPER acts centrally to regulate heart rate. Using whole-mount two color fluorescent in situ hybridization, we detected gper expression in pituitary cells that produce thyroid stimulating hormone (TSH) and regulate levels of thyroid hormone triiodothyronine (T3), a hormone known to increase heart rate. We hypothesized that activation of GPER stimulates pituitary cells to increase levels of T3, leading to an increase in heart rate. Consistent with this hypothesis, (4) GPER mutant embryos showed a mean 50% reduction in T3 levels compared to wildtype, while exposure to exogenous T3 rescued the reduced heart rate phenotype in GPER mutants. Our results demonstrate that estradiol plays a previously unappreciated role in the acute modulation of heart rate during zebrafish embryonic development and suggest that GPER autonomously regulates basal heart rate by altering total T3 levels.



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