Intimations on the Development of Effective Treatment for the Prevention of Preterm Birth: β3 Adrenergic Receptor Signaling in the Human Myometrium

Preterm birth before the thirty-seventh week of pregnancy is the leading cause of infant morbidity and mortality in the US. Infants born prematurely can spend weeks or months in the hospital, costing upwards of thirty billion a year in the US alone. Treatments for patients in labor preterm are ineffective and none are FDA approved. The β3 adrenergic receptor (β3AR) has been shown to be present in various tissues, including the human myometrium. Using contractile studies, stimulation of the β3AR has been shown to mediate relaxation. Although some pathways have been described, the mechanism(s) underlying β3AR-mediated relaxation in the myometrium are incompletely known. In other smooth muscles, the β3AR has been shown to mediate relaxation via nitric oxide (NO)-guanylyl cyclase-cGMP signaling. However, NO-mediated relaxation of the myometrium is cGMP-independent. Our studies showed that β3AR agonist, mirabegron, can be used to mediate relaxation in the human myometrium. The mechanisms associated with this relaxation are revealed to be increased production of NO in myometrial endothelial cells, stimulation of Ca2+ activated K+ channel (BKCa), and down regulation of the contractile associated protein connexin 43 (Cx43). The mechanosensitive channel Piezo1 was identified in the myometrium and showed to promote relaxation using similar mechanisms involving NO and BKCa. Our studies showed that NO mediated S-nitrosation of Cx43 promote a hemichannel state over a gap junction state. Together this research indicates the potential of β3AR as a target for developing tocolytic strategies involving combination therapy with mechanisms that have additive effects.

Level thesis:degree_level

Doctorate Degree

Year dc:date.issued

2022

Author dc:creator

• Asif, Hazik

Advisor dc:contributor.advisor

• Buxton, Iain L.O.

Committee members dc:contributor.committeemember

• Leblanc, Normand
• Burkin, Heather
• Mastick, Cynthia
• Etezadi-Amoli, Neda

Handle dc:identifier.uri

http://hdl.handle.net/11714/8381

OAI identifier oai:identifier

oai:scholarwolf.unr.edu:11714/8381