THE ROLE OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 6 IN PLACENTAL DEVELOPMENT UNDER GESTATIONAL DIABETES
Abstract
Abnormal placenta development has been indicated in preeclampsia and gestational diabetes (GDM), which are both common yet serious complications in approximately 10% of pregnancies. Proprotein convertase subtilisin/kexin-6 (PCSK6) is a protease that processes precursor proteins into active forms. Based on previous reports of PCSK6 expression in the placenta, involvement in embryonic development and vascular remodeling, we hypothesized that PCSK6 plays an important role in placenta development. Our WT placentas had a dynamic expression of PCSK6 in glycogen trophoblast cells (GlyT). In mouse hyperglycemic (HG) pregnancies, PCSK6 protein levels were decreased which led us to further pursue the interaction of PCSK6 and HG. The current study applied a PCSK6 transgenic mouse model consisting of four groups: WT and PCSK6 knockout (KO) placentas from normoglycemic (NG) and HG pregnancies. Histological examination of placenta disclosed that HG, but not PCSK6 KO, increased GlyT area within the junctional zone via differentiation. The spiral arteries (SpAs) in PCSK6 KO placentas, under NG and HG conditions, had decreased inner to outer diameter ratios and reduced trophoblast giant cell association compared to the WT placentas. Consistently, PCSK6 KO placentas over-phosphorylate β-catenin, a key protein to regulate transcription of migratory proteins. In the labyrinth, PCSK6 KO affected fetal capillary area while HG affected maternal lacunae area. PCSK6 KO-HG placentas had increased interhaemal membrane thickness. From these factors, the calculated diffusion capacity was increased in PCSK6 KO under NG but decreased under HG. In summary, our study demonstrated that PCSK6 is involved in SpA remodeling and glucose-dependent angiogenesis. Our study indicated a potential role of PCSK6 in preeclampsia and GDM related placenta dysfunctions. Future study will focus on understanding the molecular mechanisms underlying how PCSK6 deletion disrupted normal placenta development and function.
Citation
McCauley, Naomi Lisa (2021). THE ROLE OF PROPROTEIN CONVERTASE SUBTILISIN/KEXIN TYPE 6 IN PLACENTAL DEVELOPMENT UNDER GESTATIONAL DIABETES. Master's thesis, Texas A&M University. Available electronically from https : / /hdl .handle .net /1969 .1 /195735.