Expression pattern of the HIFα-family in equine chorioallantois during pregnancy and placental pathology

Equine placental dysfunction impairs fetal growth and disrupts pregnancy outcomes. Despite many advances in diagnosis, the molecular pathophysiology of equine placentitis and premature placental separation remains poorly understood. However, the hypoxia-inducible factor (HIF-α) pathway is related to placental hypoxia, and its modulation in placental diseases has been shown in other species. Therefore, we hypothesized that in conditions marked by equine placental dysfunction, oxygen deprivation in the chorioallantois membrane triggers the activation of the HIF-α pathway, which is related to molecular alterations associated with placental insufficiency. Accordingly, we compared the expression of HIF1A, HIF2A, HIF3A, and HIF1AN genes in equine chorioallantois 1) at various points during normal gestation, and in mares with 2) ascending placentitis (AP), 3) nocardioform placentitis (NP), and 4) premature placental separation (PPS), compared to mares with normal pregnancies (controls). During normal pregnancy, expression of HIF-related genes remained low until a significant post-partum increase, suggesting a balanced regulatory state under normoxic conditions. In contrast, the three pathological conditions exhibited a distinct expression profile: AP was marked by HIF1A upregulation and concurrent suppression of HIF3A and HIF1AN; NP showed reduced HIF2A and HIF3A expression without changes in HIF1A; and PPS was characterized by HIF1A upregulation with HIF1AN, HIF2A, and HIF3A downregulation. Our findings reveal that although AP, NP, and PPS all involve oxygen deprivation, the molecular hypoxia response is disease specific. This study provides novel insight into the equine placental hypoxic response. This warrants further research to elucidate these mechanisms and explore them as potential diagnostic targets for equine placental dysfunctions.