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Insulin-like Growth Factors and Their Binding Proteins Define Specific Phases of Myometrial Differentiation During Pregnancy in the Rat¹

University Health Network,⁷ Toronto General Research Institute, Toronto, Ontario, Canada M5G 2C4 Samuel Lunenfeld Research Institute,⁴ Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 Departments of Physiology⁵ and Obstetrics and Gynecology,⁶ University of Toronto, Toronto, Ontario, Canada M5S 1A1

ABSTRACT

While the insulin-like growth factor (IGF) system is known to regulate uterine function during the estrous cycle, there are limited data on its role in myometrial growth and development during pregnancy. To address this issue, we defined the expression of the Igf hormones (1 and 2), their binding proteins (Igfbp 1–6), and Igf1r receptor genes in pregnant, laboring, and postpartum rat myometrium by real-time PCR. IGF family genes were differentially expressed throughout gestation. Igf1 and Igfbp1 mRNA levels were upregulated during proliferative phase (Days 6–12) of rat gestation. Igfbp3 gene expression also was elevated in proliferating smooth muscle cells (SMCs) and was highest at the time of transition between proliferative and synthetic phases (Days 12–15). Igfbp6 gene expression profile paralleled plasma progesterone (P4) concentrations, peaking during the synthetic phase (Days 17–19) and decreasing thereafter. Administration of P4 at late pregnancy (starting from Day 20) to maintain elevated plasma P4 concentrations blocked the onset of labor and prevented the fall in Igfbp6 mRNA levels. In contrast, the treatment of pregnant rats with the P4 receptor antagonist RU486 on Day 19 induced preterm labor and the premature decrease of Igfbp6 gene expression. Igfbp2 gene expression was transiently upregulated during the contractile phase of gestation (Days 21–23) solely in the gravid horn of unilaterally pregnant rats, but it was not affected in P4- or RU486-treated animals, supporting a role for mechanical stretch imposed by the growing fetuses. Igfbp5 gene was induced during postpartum involution. Our results suggest the importance of the IGF system in phenotypic and functional changes of myometrial SMCs throughout gestation in preparation for labor.

insulin-like growth factor receptor, parturition, pregnancy, progesterone, uterus

³These authors contributed equally to this work.

¹Supported by a grant from the Canadian Institutes of Health Research (CIHR).

Correspondence: ²Stephen J. Lye, Samuel Lunenfeld Research Institute at Mount Sinai, 600 University Ave., Suite 870, Toronto, ON, Canada M5G 1X5. FAX: 416 586 8740; e-mail: lye{at}mshri.on.ca

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