Gap junction communication between uterine stromal cells plays a critical role in pregnancy-associated neovascularization and embryo survival

被引:127
作者
Laws, Mary J. [1 ]
Taylor, Robert N. [3 ]
Sidell, Neil [3 ]
DeMayo, Francesco J. [4 ]
Lydon, John P. [4 ]
Gutstein, David E. [5 ]
Bagchi, Milan K. [2 ]
Bagchi, Indrani C. [1 ]
机构
[1] Univ Illinois, Dept Vet Biosci, Urbana, IL 61802 USA
[2] Univ Illinois, Dept Mol & Integrat Physiol, Urbana, IL 61802 USA
[3] Emory Univ, Sch Med, Dept Gynecol & Obstet, Atlanta, GA 30322 USA
[4] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
[5] NYU, Sch Med, New York, NY 10016 USA
来源
DEVELOPMENT | 2008年 / 135卷 / 15期
关键词
implantation; endometrium; neovascularization; estrogen; connexin; 43; mouse;
D O I
10.1242/dev.019810
中图分类号
Q [生物科学];
学科分类号
07 [理学]; 0710 [生物学]; 09 [农学];
摘要
In the uterus, the formation of new maternal blood vessels in the stromal compartment at the time of embryonic implantation is critical for the establishment and maintenance of pregnancy. Although uterine angiogenesis is known to be influenced by the steroid hormones estrogen ( E) and progesterone ( P), the underlying molecular pathways remain poorly understood. Here, we report that the expression of connexin 43 (Cx43), a major gap junction protein, is markedly enhanced in response to E in uterine stromal cells surrounding the implanted embryo during the early phases of pregnancy. Conditional deletion of the Cx43 gene in these stromal cells and the consequent disruption of their gap junctions led to a striking impairment in the development of new blood vessels within the stromal compartment, resulting in the arrest of embryo growth and early pregnancy loss. Further analysis of this phenotypical defect revealed that loss of Cx43 expression resulted in aberrant differentiation of uterine stromal cells and impaired production of several key angiogenic factors, including the vascular endothelial growth factor (Vegf). Ablation of CX43 expression in human endometrial stromal cells in vitro led to similar findings. Collectively, these results uncovered a unique link between steroid hormone-regulated cell-cell communication within the pregnant uterus and the development of an elaborate vascular network that supports embryonic growth. Our study presents the first evidence that Cx43-type gap junctions play a critical and conserved role in modulating stromal differentiation, and regulate the consequent production of crucial paracrine signals that control uterine neovascularization during implantation.
引用
收藏
页码:2659 / 2668
页数:10
相关论文
共 49 条
[1]
[Anonymous], 1999, ENCY REPROD
[2]
The cellular Internet: On-line with connexins [J].
Bruzzone, R ;
White, TW ;
Goodenough, DA .
BIOESSAYS, 1996, 18 (09) :709-718
[3]
Embryo implantation [J].
Carson, DD ;
Bagchi, I ;
Dey, SK ;
Enders, AC ;
Fazleabas, AT ;
Lessey, BA ;
Yoshinaga, K .
DEVELOPMENTAL BIOLOGY, 2000, 223 (02) :217-237
[4]
DIFFERENTIAL EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR AND ITS RECEPTOR MESSENGER-RNAS IN THE MOUSE UTERUS AROUND THE TIME OF IMPLANTATION [J].
CHAKRABORTY, I ;
DAS, SK ;
DEY, SK .
JOURNAL OF ENDOCRINOLOGY, 1995, 147 (02) :339-352
[5]
Inhibition of β-catenin signaling causes defects in postnatal cartilage development [J].
Chen, Mo ;
Zhu, Mei ;
Awad, Hani ;
Li, Tian-Fang ;
Sheu, Tzong-Jen ;
Boyce, Brendan F. ;
Chen, Di ;
O'Keefe, Regis J. .
JOURNAL OF CELL SCIENCE, 2008, 121 (09) :1455-1465
[6]
Induction of cytotoxic T-lymphocyte antigen-2β, a cysteine protease inhibitor in decidua -: A potential regulator of embryo implantation [J].
Cheon, YP ;
DeMayo, FJ ;
Bagchi, MK ;
Bagchi, IC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (11) :10357-10363
[7]
IMPLANTATION AND THE PLACENTA - KEY PIECES OF THE DEVELOPMENT PUZZLE [J].
CROSS, JC ;
WERB, Z ;
FISHER, SJ .
SCIENCE, 1994, 266 (5190) :1508-1518
[8]
EXPRESSION OF RAT PROLACTIN-LIKE PROTEIN-B IN DECIDUOMA OF PSEUDOPREGNANT RAT AND IN DECIDUA DURING EARLY-PREGNANCY [J].
CROZE, F ;
KENNEDY, TG ;
SCHROEDTER, IC ;
FRIESEN, HG .
ENDOCRINOLOGY, 1990, 127 (06) :2665-2672
[9]
Gap junctions: structure and function (Review) [J].
Evans, WH ;
Martin, PEM .
MOLECULAR MEMBRANE BIOLOGY, 2002, 19 (02) :121-136
[10]
Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene [J].
Ferrara, N ;
CarverMoore, K ;
Chen, H ;
Dowd, M ;
Lu, L ;
OShea, KS ;
PowellBraxton, L ;
Hillan, KJ ;
Moore, MW .
NATURE, 1996, 380 (6573) :439-442