Effects of homologous and heterologous in-vitro fertilization (IVF) on human placental immune response and angiogenesis

In order to understand the effects of Artificial Reproductive Technology (ART) techniques on placental development, we analyzed the expression profiles of main immunological and angiogenic factors in placental tissues collected from spontaneous conceived, homologous Intracytoplasmic sperm injection (ICSI) and In vitro Fertilization with Embryo Transfer (FIVET) and heterologous Egg Donation (ED) pregnancies. Placental tissue biopsies were randomly collected from physiological spontaneous conceived pregnancies (CTRL, n=30), homologous ICSI pregnancies (n=20), homologous FIVET pregnancies (n=20) and heterologous Egg Donation (ED) (n=16). Total RNA was extracted from frozen placental biopsies and IDO1 and 2, IFNɣ, TNFα, OPN, VEGF, PlGF and s-Flt1 gene expression levels were assessed by Real-time PCR. Moreover, IL18 and IL18-BP placental protein levels were determined using ELISA assay. We reported no significant differences in mRNA IDO1 and IDO2 expression levels between controls and homologous ICSI/FIVET placentae. IFNɣ was significantly downregulated in homologous FIVET and ICSI placentae relative to ED placentae and in homologous FIVET relative to controls. IL18 protein levels were significantly decreased in homologous ICSI. VEGF mRNA levels were significantly increased in ICSI placentae relative to ED and controls. Moreover, ICSI placentae over-expressed sFlt-1 mRNA levels relative to controls. Instead, ED pregnancies showed decreased sFlt-1 mRNA levels compared to homologous ICSI pregnancies. For the first time to our knowledge, we reported a different expression of immunomodulators and angiogenetic factors in physiological ART-conceived pregnancies and physiological spontaneously conceived. The stronger immunotolerance achieved by IFNɣ-mediated IDO upregulation in IVF pregnancies could compensate the immunological dissimilarity and therefore lead to an homeostatic angiogenetic environment in order to set up a physiological pregnancy, compensating the imbalances induced by an artificially achieved pregnancy.