P113. Effects of embryonic hypoxia on maxillofacial development

Abstract

It has been well known that many genetic and environmental factors are involved in maxillofacial development. Disturbance in these factors could result in congenital anomalies such as cleft lip and palate in human. Some environmental factors, administration of vasoconstrictors and uterine anemia during pregnancy, induce embryonic anemia, and it has been suggested that embryonic hypoxia inhibits development of circulatory organs, limb and maxillofacial organs. In this study we studied the effect of hypoxic condition on mouse lip formation. Lip forms by the fusion between facial processes, medial nasal, lateral nasal, and maxillary processes. We cultured mouse embryos at the beginning of facial process fusion stage by whole embryo culture system under standard oxygen supply and hypoxic conditions, and found that hypoxia induced the failure in the fusion, cleft lip, at higher frequency than standard oxygen supply. Then, we further investigated the effects of embryonic hypoxia on expression change of the genes that are associated with angiogenesis as a consequence of hypoxia and maxillofacial morphogenesis in the facial processes. Expression levels of vascular endothelial growth factor (VEGF) that is upregulated in response to hypoxic condition in vivo were significantly increased in the embryos cultured under hypoxic condition (hypoxic embryos). Transcription factors, Msx1 and Msx2, are expressed in the facial mesenchyme and required for proliferation and differentiation. These transcription factors were downregulated in the facial mesenchyme of hypoxic embryos. Active Wnt signaling has been shown to be involved in lip formation, and the amount of phosphor-Gsk3 alpha/beta, active Wnt signaling marker, were decreased in hypoxic embryos. These results suggest that embryonic hypoxia during the period of facial process fusion induces similar molecular response to adult hypoxic condition and affects expression levels of genes that are strongly associated with lip formation.