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18 September 2013 Decidual Angiogenesis and Placental Orientation Are Altered in Mice Heterozygous for a Dominant Loss-of-Function Gja1 (Connexin43) Mutation
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Abstract

Connexin43 (CX43), encoded by Gja1 in the mouse, is highly expressed in decidual cells and is known to be important for the transformation of stromal cells into the compact decidua and for neoangiogenesis. Here we investigated if the dominant Gja1Jrt mutation encoding CX43G60S in mice, which results in a phenotype resembling oculodentodigital dysplasia in humans, has an impact on decidualization, angiogenesis, and implantation. We found a reduced mean weight of fetuses at Gestational Day 17.5 in dams carrying this mutation, with the growth deficiency being independent of fetal genotype. Although the mutant implantation sites exhibited a reduction in CX43 protein, with most immunoreactivity being cytoplasmic, the decidua was morphologically intact at Embryonic Days 5.5 to 7.5. However, the mutation resulted in enhanced and irregular angiogenesis and an increased level of expression of the angiogenic factor-encoding genes Vegfa, Flt1, Kdr, and Fgf2 as well as the prolactin-related gene Prl6a. Moreover, immunolocalization of VEGFA, FLT1, and KDR revealed a homogeneous distribution pattern in the mesometrial as well as antimesometrial decidua of the mutants. Most obviously, uterine NK cells are drastically diminished in the mesometrial decidua of the mutant mice. Invasion of ectoplacental cone cells was disoriented, and placentation was established more laterally in the implantation chambers. It was concluded that the CX43G60S mutant impairs control of decidual angiogenesis, leading to dysmorphic placentation and fetal growth restriction. This phenomenon could contribute to the reduced fetal weights and viability of pups born of Gja1Jrt/ dams.

Elke Winterhager, Alexandra Gellhaus, Sandra M. Blois, Lesley A. Hill, Kevin J. Barr, and Gerald M. Kidder "Decidual Angiogenesis and Placental Orientation Are Altered in Mice Heterozygous for a Dominant Loss-of-Function Gja1 (Connexin43) Mutation," Biology of Reproduction 89(5), (18 September 2013). https://doi.org/10.1095/biolreprod.113.111690
Received: 24 June 2013; Accepted: 1 September 2013; Published: 18 September 2013
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