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Intra-Amniotic Infection Upregulates Decidual Cell Vascular Endothelial Growth Factor (VEGF) and Neuropilin-1 and -2 Expression: Implications for Infection-Related Preterm Birth

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Frederick Schatz, PhD

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Felice Arcuri, PhD

Departments of Human Pathology and Oncology, University of Siena, Siena, Italy

Paolo Toti, MD

Departments of Human Pathology and Oncology, University of Siena, Siena, Italy

Umit A. Kayisli, PhD

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

William Murk, MS

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Guoyang Luo, MD, PhD

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Charles J. Lockwood, MD

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut

Errol R. Norwitz, MD, PhD

Department of Obstetrics, Gynecology & Reproductive Sciences, Yale University School of Medicine, New Haven, Connecticut, errol.norwitz{at}yale.edu

Intra-amniotic infection/inflammation (IAI) is a major cause of preterm birth, but the mechanisms responsible are not well understood. This study investigates the effects of IAI on vascular endothelial growth factor (VEGF) as well as VEGF receptor (Flt1, KDR2) and coreceptor (neuropilin-1 and -2) messenger RNA (mRNA) and protein expression at the maternal-fetal interface, both in vitro and in vivo. Decidual stromal cells (DSCs) were isolated from term placentae, purified, and treated with 10^—8 mol/L estradiol (E₂), 10 ^—7 mol/L medroxyprogesterone acetate (MPA), both, or vehicle for 7 days. Vascular endothelial growth factor expression in cultured DSCs increased in response to stimulation with interleukin 1β (IL-1β; 0.01-10 ng/mL)—but not tumor necrosis factor (TNF-; 1 ng/mL)—in a concentration-dependent fashion irrespective of the hormonal milieu. This effect appears to be mediated at the level of gene transcription because stimulation with IL-1β (but not TNF-) increased expression of VEGF mRNA as measured by real-time quantitative reverse transcriptase-polymerase chain reaction (RT-qPCR); a similar increase was seen in neuropilin-1/-2 (but not Flt1 and KDR2) mRNA. Immunohistochemical studies confirmed these observations in vivo. Immunostaining for VEGF and neuropilin-1/-2 (but not Flt1 or KDR2) was increased in serial tissue sections of decidua from women with clinical and histological evidence of IAI versus noninfected controls, and in cultured term DSCs exposed to IL-1β. The novel observations that IL-1β stimulates VEGF and neuropilin-1/-2 mRNA and protein expression in term DSCs in vitro along with confirmatory in vivo data using immunohistochemistry provide a mechanism by which IAI can alter vascular permeability, thereby facilitating leukocyte trafficking and increasing the risk of abruption, both of which are associated with preterm birth.

Key Words: VEGF • VEGF receptor • neuropilin • intra-amniotic infection • preterm birth.

This version was published on August 1, 2009

Reproductive Sciences, Vol. 16, No. 8, 767-780 (2009)
DOI: 10.1177/1933719109336623


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