PT  - JOURNAL ARTICLE
AU  - Shannon N Romano
AU  - Hailey E Edwards
AU  - J Paige Souder
AU  - Xiangqin Cui
AU  - Daniel A Gorelick
TI  - G protein-coupled estrogen receptor regulates heart rate and heart valve thickness in zebrafish
AID  - 10.1101/088955
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 088955
4099  - http://biorxiv.org/content/early/2017/02/14/088955.short
4100  - http://biorxiv.org/content/early/2017/02/14/088955.full
AB  - Estrogens act by binding to estrogen receptors alpha and beta (ERα, ERβ), ligand-dependent transcription factors that play crucial roles in sex differentiation, tumor growth and cardiovascular physiology. Estrogens also activate the G protein-coupled estrogen receptor (GPER), however the function of GPER in vivo is less well understood. Here we find that GPER is required for normal heart rate in zebrafish embryos and for normal valve thickness in zebrafish adults. Acute exposure to estrogens increased heart rate in wildtype and in ERα and ERβ mutant embryos but not in GPER mutants. Nuclear estrogen receptor signaling remained normal in GPER mutant embryos. However, GPER mutant embryos exhibited reduced basal heart rate while heart rate was normal in ERα and ERβ mutants. We detected gper transcript in discrete regions of the brain but not in the heart. In the brain, we observed gper expression in cells lacking nuclear estrogen receptor activity, suggesting that GPER acts in the brain to regulate heart rate independently of nuclear estrogen receptor signaling. Additionally, blood flow in embryos has been shown to influence heart valve maturation, suggesting the hypothesis that reduced heart rate during embryonic and juvenile development disrupts heart valve maturation. Consistent with this hypothesis, we find that adult GPER mutants have thinner heart valves than wildtype. Our results demonstrate that estradiol plays a previously unappreciated role in the acute modulation of heart rate during zebrafish embryonic development and that GPER functions as an autonomous estrogen receptor in vivo to regulate basal heart rate and heart valve thickness.