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Preeclampsia (PE) is a pregnancy specific hypertensive disorder. If untreated PE leads to life threatening condition, eclampsia. Systemic complement activation levels are increased during pregnancy compared to non-pregnant women of childbearing age. In PE, systemic complement levels are further increased, and higher complement deposition has been observed on placentas. We hypothesize that combinations of common SNPs in maternal and fetal complement genes constitute pregnancy specific complotypes and predispose women to PE. In this study, we sequenced two maternal (factor H and C3) and one fetal (CD46) complement genes and identified a total of 9 common SNPs. Minor allele frequencies of two fetal CD46 SNPs were significantly higher in PE. Further, complotypes consisting of fetal CD46 variants and maternal CFH/C3 variants were highly prevalent in PE patients compared to normotensive pregnancies. Placental complement deposition and maternal alternative pathway 50 (AP50) values were higher in PE pregnancies. Irrespective of disease status, two CD46 variants were associated with reduced placental CD46 expression and one CFH variant was associated with increased maternal AP50 values.

Many circumstantial evidences from human and animal studies suggest that complement cascade dysregulation may play an important role in pregnancy associated complications including preeclampsia. Deletion of rodent specific complement inhibitor gene, Complement Receptor 1-related Gene/Protein y (Crry) produces embryonic lethal phenotype due to complement activation. It is not clear if decreased expression of Crry during pregnancy produces hypertensive phenotype. We downregulated Crry in placenta by injecting inducible lentivialshRNA vectors into uterine horn of pregnant C57BL/6 mice at the time of blastocyst hatching. Placenta specific downregulation of Crry without significant loss of embryos was achieved upon induction of shRNA using an optimal doxycycline dose at mid gestation. Crry downregulation resulted in placental complement deposition. Late-gestation measurements showed that fetal weights were reduced and blood pressure increased in pregnant mice upon downregulation of Crry suggesting a critical role for Crry in fetal growth and blood pressure regulation.

Defective pancreatic β-cell adaptation in pregnancy plays an important role in the pathophysiology of gestational diabetes mellitus (GDM), but the molecular basis remains unclear. Objectives of this study were to determine if circulating levels of adrenomedullin (ADM) in women with GDM are elevated and to assess the effects of ADM on insulin synthesis and secretion by human pancreatic β-cells. A stable gene product of ADM precursor, midregional pro-adrenomedullin (MR-proADM), was measured in plasma of pregnant women with normal glucose tolerance (NGT, n = 10) or GDM (n = 11). The β-Lox5 cell line, derived from human pancreatic β-cells, was transduced with homeodomain transcription factor pancreatic-duodenal homeobox (PDX) factor 1 (PDX1) encoding lentiviral vector and treated with different doses of ADM. mRNA for insulin, ADM, and its receptor components in β-Lox5 cells and insulin in media were measured. Plasma MR-proADM levels were significantly higher in GDM compared with patients with NGT. Pancreatic β-Lox5 cells express mRNA for insulin, ADM, and its receptor components. PDX1 transduction and cell-cell contact synergistically promote β-Lox5 cells insulin mRNA and secretion. Furthermore, ADM dose-dependently inhibited mRNA and secretion of insulin in β-Lox5 cell aggregates. These inhibitory effects were blocked by ADM antagonist ADM22-52, cAMP-dependent protein kinase A inhibitor KT5720, and Erk inhibitor PD98059, but not by PI-3K the inhibitor wortmannin. Circulating ADM concentrations were elevated in pregnant women with GDM. ADM suppresses insulin synthesis and secretion by pancreatic β-cells in vitro. Thus, increased circulating ADM may contribute to the defective adaptation of β-cells in diabetic pregnancies, and blockade of ADM actions with its antagonists may improve β-cell functions.

Context: Defective pancreatic [beta]-cell adaptation in pregnancy plays an important role in the pathophysiology of gestational diabetes mellitus (GDM), but the molecular basis remains unclear. Objectives of this study were to determine if circulating levels of adrenomedullin (ADM) in women with GDM are elevated and to assess the effects of ADM on insulin synthesis and secretion by human pancreatic [beta]-cells. Design: A stable gene product of ADM precursor, midregional pro-adrenomedullin (MR-proADM), was measured in plasma of pregnant women with normal glucose tolerance (NGT, n = 10) or GDM (n = 11). The [beta]-Lox5 cell line, derived from human pancreatic [beta]-cells, was transduced with homeodomain transcription factor pancreatic-duodenal homeobox (PDX) factor 1 (PDX1) encoding lentiviral vector and treated with different doses of ADM. mRNA for insulin, ADM, and its receptor components in [beta]-Lox5 cells and insulin in media were measured. Results: Plasma MR-proADM levels were significantly higher in GDM compared with patients with NGT. Pancreatic [beta]-Lox5 cells express mRNA for insulin, ADM, and its receptor components. PDX1 transduction and cell-cell contact synergistically promote [beta]-Lox5 cells insulin mRNA and secretion. Furthermore, ADM dose-dependently inhibited mRNA and secretion of insulin in [beta]-Lox5 cell aggregates. These inhibitory effects were blocked by ADM antagonist ADM22-52, cAMP-dependent protein kinase A inhibitor KT5720, and Erk inhibitor PD98059, but not by PI-3K the inhibitor wortmannin. Conclusions: Circulating ADM concentrations were elevated in pregnant women with GDM. ADM suppresses insulin synthesis and secretion by pancreatic [beta]-cells in vitro. Thus, increased circulating ADM may contribute to the defective adaptation of [beta]-cells in diabetic pregnancies, and blockade of ADM actions with its antagonists may improve [beta]-cell functions. (J Clin Endocrinol Metab 104: 697-706, 2019)

Preeclampsia is a multifactorial, pregnancy-related disorder characterized by new-onset hypertension and proteinuria, with distinct early- and late-onset forms linked to varying placental and maternal pathologies. While complement system dysregulation has been implicated in the pathogenesis of preeclampsia, its causal relationship and molecular mechanisms remain unclear. In mice, complement receptor 1-related protein y (Crry) functions as a critical complement regulator at the fetal-maternal interface, essential for early embryonic survival. Complete Crry deficiency is embryonically lethal, complicating in vivo studies of complement activation in pregnancy. Using an alternative strategy, we developed a placenta-specific, doxycycline-inducible shRNA mouse model utilizing Cyp19-driven Cre recombinase and a Tet-On system to downregulate Crry in a dose-dependent manner 9.5 days post coitus, effectively restricting complement activation to the placenta. Using this model, we demonstrate that early gestation but sustained placental complement activation impairs maternal heart and liver adaptation, reduces placental efficiency, and causes fetal growth restriction, mimicking early-onset preeclampsia. Conversely, delayed complement activation induces a phenotype more consistent with late-onset preeclampsia features without placental pathology. In early-onset preeclampsia-like phenotype, the fetal growth restriction is accompanied by placental glycogen storage deficiency, and impaired hormonal function. Maternal glucose metabolism is not affected but compensatory adaptations in lipid metabolism occur although insufficient to offset fetal growth restriction. This novel model reveals that the timing of placental complement activation dictates the spectrum of preeclampsia-like pathology, providing mechanistic insights into the pathophysiology of preeclampsia.