Placental Defects in α7 Integrin Null Mice
Introduction
The placenta is a multifunctional organ essential for maintaining pregnancy, providing nutrients and growth factors to the fetus, removing waste and protecting the fetus from potentially harmful substances [1]. Placental dysfunction can result in insufficient fetal nutrition, which can lead to intrauterine growth restriction (IUGR) [2], [3], [4], [5], [6]. At least 8% of human pregnancies end in infant death due to complications that arise from IUGR [1], [7], [8]. Epidemiological studies indicate IUGR can have lifelong consequences by increasing the risk for heart disease, type-2 diabetes, hypertension, and stroke [9], [10], [11], [12]. Abnormalities in placental structure and function have been associated with the majority of reported cases of fetal IUGR [1].
Integrins are a diverse family of cell surface receptors that mediate the interactions between cells and the extracellular matrix [13], [14]. Previous studies have implicated integrins as important adhesion molecules in placental development [15], [16], [17], [18]. In mice, targeted mutations in α4, α5, α6, αv, β3, and β8 integrin genes result in placental defects and embryonic lethality [18], [19], [20], [21], [22].
The α7β1 integrin is a laminin receptor that is highly expressed in vascular smooth muscle [23]. Loss of the α7 integrin causes partial embryonic lethality in which 44% of the α7 integrin null embryos die before birth [24], [25]. We have recently demonstrated that loss of the α7 integrin chain leads to cerebral vascular defects which may contribute to the partial embryonic lethality observed in α7 integrin null mice [25]. Studies have shown α7 integrin expression increases in vascular smooth muscle cells (VSMCs) isolated from rats treated with allylamine to induce vascular damage [26]. In addition, treatment of rat VSMCs with platelet derived growth factor (PDGF) increased α7 integrin expression and promoted α7 integrin-mediated adhesion to laminin-1 [27]. Together these results suggest an important role for the α7β1 integrin in vascular development and the progression of vasculoproliferative diseases.
The α7β1 integrin is expressed in the embryonic yolk sac, trophoectoderm cells of the blastocyst and later in the trophoblast layer of the placenta [15]. Although the interaction of the α7β1 integrin with laminin is necessary for trophoblast adhesion during implantation [15], little is known about how loss of the α7 integrin chain affects placental development. Since the placenta is well-vascularized, we hypothesized that loss of the α7 integrin might lead to structural defects that contribute to reduced placental vascular function and partial embryonic lethality.
To investigate if loss of the α7 integrin causes vascular defects in the placenta, we analyzed VSMCs in blood vessels of the placentae from α7 integrin null embryos. Biochemical and histological measurements were used to determine if loss of the α7 integrin in the placenta resulted in vascular defects. The observed vascular smooth muscle abnormalities in placental blood vessels support the hypothesis that the α7β1 integrin has an important role in placental development and suggest loss of this integrin results in placental defects that contribute to the partial embryonic lethality observed in α7 integrin null mice.
Section snippets
Isolation of placentae
Timed homozygous matings were set up to produce wild-type (C57BL6 strain) and α7 integrin null (C57BL6-α7βgal strain) embryos and placentae. Pregnant female mice were euthanized in accordance with a protocol approved by the University of Nevada, Reno Animal Care and Use Committee. ED9.5 and ED13.5 placentae were dissected out of the uterus, rinsed in PBS and frozen in liquid nitrogen cooled isopentane.
Histological staining
ED9.5 placentae were cryoprotected by fixing with 4% paraformaldehyde for 2 h, then washed with
α7 integrin is expressed in placental VSMCs
Loss of α7 integrin results in partial embryonic lethality that begins at ED10.5 [24], [25]. To determine which cells within the placenta express the α7 integrin during this critical period, placentae from embryos at ED9.5 and ED13.5 were analyzed by immunofluorescence using anti-α7 integrin antibodies. The α7 integrin was detected in VSMCs within the fetal blood vessels and placental labyrinth from wild-type ED9.5 and ED13.5 embryos and was absent in the placentae from α7 integrin null mice (
Discussion
This study demonstrates that the α7β1 integrin plays an important role in the vascularization of the placenta. Placental vascularization is a critical event during embryonic development allowing the proper exchange of nutrients, oxygen and removal of wastes between maternal and fetal blood supplies [31], [32], [33], [34].
Previous studies have shown that the α7 integrin is expressed in cells derived from the trophoectoderm of the developing placenta [15]. Our results showed strong
Acknowledgements
The authors would like to thank Dr. Stephen Kaufman, University of Illinois, Urbana, IL, for the α7B (B2 347) antibody and Dr. Maria Valencik, University of Nevada, Reno, NV, for the α5 integrin antibody. The authors would also like to thank Maria Peabody from the University of Nevada, Department of Pathology and Dr. William Hatton from the University of Nevada, Imaging and Morphology Core for technical assistance. This work was supported by grants from the NIH/NCRR P20 RR018751-01 and P20
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