Oxytocin in cardiac ontogeny

Abstract

Previous studies demonstrated the presence of oxytocin (OT) and oxytocin receptors (OTRs) in the heart. The present work provides results supporting a potential role of OT in cardiomyogenesis. Here, we show a maximal OT and OTR protein level in the developing rat heart at day 21 of gestation and postnatal days 1-4, when cardiac myocytes are at a stage of intense hyperplasia. Between postnatal days 1 and 66, OT decreased linearly in all heart chambers (4.1-to 6.6-fold). Correspondingly, immunocytochemistry demonstrated that OTRs, which were eminent in postnatal cardiomyocytes, declined with age to low levels in adults. Interestingly, in coronary vasculature, OTRs developed in endothelial cells at postnatal days 12 and 22 and achieved a plateau in adult rats. These findings suggest that OT can be involved in developmental formation of the coronary vessels. In vivo, the OT͞OTR system in the fetal heart was sensitive to the actions of retinoic acid (RA), recognized as a major cardiac morphogen. RA treatment produced a significant increase (2-to 3-fold) both in the OT concentration and in the OT mRNA levels. Ex vivo, an OT antagonist inhibited RA-mediated cardiomyocyte differentiation of P19 embryonic stem cells. The decline of cardiac OT expression from infancy to adulthood of the rat and changes in cell types expressing OTR indicate a dynamic regulation of the OT system in the heart rather than constitutive expression. The results support the hypothesis that RA induces cardiomyogenesis by activation of the cardiac OT system. heart development ͉ oxytocin receptors ͉ retinoic acid ͉ oxytocin antagonist ͉ cardiomyocyte differentiation O xytocin (OT), recognized traditionally as a reproductive hormone with a major role in childbirth and lactation, is produced in high concentrations in the hypothalamic supraoptic nucleus and paraventricular nucleus, then transported from these source nuclei to the posterior pituitary by neurosecretion (1). Longitudinal studies of neural and hormonal circuits activated by experimental volume expansion have identified OT as a major regulator of cardiovascular functions (reviewed in refs. 2 and 3). OT, injected peripherally, causes a decrease of arterial pressure (4) while reducing both heart rate and the force of contractions in isolated atria (5). OT acts via neuroendocrine͞ endocrine͞paracrine pathways to release atrial natriuretic peptide (ANP) from the heart (6, 7). ANP is a potent diuretic, natriuretic, and vasorelaxant hormone that is also involved in cell growth regulation. In addition, we have demonstrated that in isolated, perfused hearts, an OT antagonist (OTA) blocks basal ANP release (7), suggesting the presence of local OT in the heart. Further study revealed cardiac OT synthesis (8), with OT being detected in the medium of cultured neonatal rat cardiomyocytes (9).Recently, we showed that P19 embryonic carcinoma cells, a model of mouse embryonic stem cells, express OT receptors (OTRs), and OT stimulates the differentiation of these cells into beating cell colonies expressing ...

Neonatal oxytocin treatment modulates oxytocin receptor, atrial natriuretic peptide, nitric oxide synthase and estrogen receptor mRNAs expression in rat heart

“…The importance of the OT system during rodents development was validated by a study showing that OT and OTR are expressed in the fetal rat heart and decrease to relatively low levels in adulthood [21]. These findings suggest that cardiac OT may be functional in fetal life, in contrast to low OT synthesis [1] and the low concentration of biologically active OT in the hypothalamus [21]. It might be speculated that OT production in the heart during fetal life and early maturation may supplement low OT production in hypothalamic nuclei.…”

Cardiovascular Action of Oxytocin

“…Interestingly, the cardiac oxytocin expression in the fetal heart was upregulated by retinoic acid, a well-recognized major cardiomyogen. An oxytocin antagonist inhibited retinoic acid-mediated cardiomyocyte differentiation of embryonic stem cells, suggesting that cardiac oxytocin system play the role in retinoic acid-induced cardiomyogenesis [8].…”

“…The expression of oxytocin and its receptor is eminent in postnatal cardiomyocytes, and decreases with age to low levels in adults [8]. However, oxytocin receptors develop in the endothelial cells at postnatal and achieve a plateau in adult rats, indicating a dynamic regulation of oxytocin system in the heart rather than constitutive expression [8]. Interestingly, the cardiac oxytocin expression in the fetal heart was upregulated by retinoic acid, a well-recognized major cardiomyogen.…”

“…Oxytocin receptors are members of a subclass of G-protein-coupled receptor and activation of the receptor transducer signaling via Gαq and Gαi subunits to activate phospholipase Cβ and mitogen-activated protein kinase，resulting in increased intracellular calcium concentration [7]. The expression of oxytocin and its receptor is eminent in postnatal cardiomyocytes, and decreases with age to low levels in adults [8]. However, oxytocin receptors develop in the endothelial cells at postnatal and achieve a plateau in adult rats, indicating a dynamic regulation of oxytocin system in the heart rather than constitutive expression [8].…”

“…Interestingly, the cardiac oxytocin expression in the fetal heart was upregulated by retinoic acid, a well-recognized major cardiomyogen. An oxytocin antagonist inhibited retinoic acid-mediated cardiomyocyte differentiation of embryonic stem cells, suggesting that cardiac oxytocin system play the role in retinoic acid-induced cardiomyogenesis [8].The homeostatic functions of the intrinsic cardiovascular oxytocin system are beginning to be understood. It has been proposed that balance between nitric oxide (NO) and oxidative stress is critical for maintenance of cardiovascular homeostasis [9].…”