Effect of Beta 3 Adrenoreceptor Modulation on Patency of the Ductus Arteriosus.

Alessandro Pini,Sergio Fabbri,Arianna Carolina Rosa,Alessandro Guerrini,Maura Calvani,Camilla Fazi,Patrizia Nardini,Giulia Forni,Giancarlo La Marca,Luca Filippi

doi:10.3390/cells9122625

Abstract

β3-adrenoreceptor (β3-AR), a G-protein coupled receptor, has peculiar regulatory properties in response to oxygen and widespread localization. β3-AR is expressed in the most frequent neoplasms, also occurring in pregnant women, and its blockade reduces tumor growth, indicating β3-AR-blockers as a promising alternative to antineoplastic drugs during pregnancy. However, β3-AR involvement in prenatal morphogenesis and the consequences of its blockade for the fetus remain unknown. In this study, after the demonstrated expression of β3-AR in endothelial and smooth muscle cells of ductus arteriosus (DA), C57BL/6 pregnant mice were acutely treated at 18.5 of gestational day (GD) with indomethacin or with the selective β3-AR antagonist SR59230A, or chronically exposed to SR59230A from 15.5 to 18.5 GD. Six hours after the last treatment, fetuses were collected. Furthermore, newborn mice were treated straight after birth with BRL37344, a β3-AR agonist, and sacrificed after 7 h. SR59230A, at the doses demonstrated effective in reducing cancer progression (10 and 20 mg/kg) in acute and chronic mode, did not induce fetal DA constriction and did not impair the DA ability to close after birth, whereas at the highest dose (40 mg/kg), it was shown to cause DA constriction and preterm-delivery. BRL37344 administered immediately after birth did not alter the physiological DA closure.

Highlights

There has been limited research on β3-AR involvement in morphogenesis, with the only available studies reporting weak umbilical vessel vasodilatation [24] and an increase of fetal adipocyte thermogenesis exerted by its activation [25]
The consequences of β3-AR targeting, in particular its blockade, for the fetus remains an unexplored field, in spite of the fact that this receptor is highly expressed during the first week of pregnancy [34], probably as a consequence of the relatively hypoxic fetal environment
A first significant finding of the present study is that β3-AR is expressed by both endothelial and smooth muscle cells of fetal ductus arteriosus (DA), suggesting its possible involvement in maintenance of DA patency

Summary

Introduction

Β3-AR is expressed in the most frequent neoplasms, occurring in pregnant women, and its blockade reduces tumor growth, indicating β3-AR-blockers as a promising alternative to antineoplastic drugs during pregnancy. After the demonstrated expression of β3-AR in endothelial and smooth muscle cells of ductus arteriosus (DA), C57BL/6 pregnant mice were acutely treated at 18.5 of gestational day (GD) with indomethacin or with the selective β3-AR antagonist SR59230A, or chronically exposed to SR59230A from 15.5 to 18.5 GD. Newborn mice were treated straight after birth with BRL37344, a β3-AR agonist, and sacrificed after. SR59230A, at the doses demonstrated effective in reducing cancer progression (10 and 20 mg/kg) in acute and chronic mode, did not induce fetal DA constriction and did not impair the DA ability to close after birth, whereas at the highest dose (40 mg/kg), it was shown to cause DA constriction and preterm-delivery.

Methods

Results

Conclusion