Nerve growth factor induces vascular endothelial growth factor expression in granulosa cells via a trkA receptor/mitogen-activated protein kinase-extracellularly regulated kinase 2-dependent pathway

Marcela Julio-Pieper, Patricia Lozada, Veronica Tapia, Margarita Vega, Cristián Miranda, David Vantman, Sergio Ojeda, Carmen Romero

    Research output: Contribution to journalArticle

    39 Citations (Scopus)

    Abstract

    Context: Acquisition of ovulatory competence by antral follicles requires development of an adequate vascular supply. Although it is well established that ovarian angiogenesis is cyclically regulated by vascular endothelial growth factor (VEGF), the factors controlling VEGF production by ovarian follicles remain largely unknown. Nerve growth factor (NGF) may be one of these factors, because NGF promotes angiogenesis and synthesis of angiogenic factors in other tissues and is produced by human granulosa cells (hGCs). Objective: The aim of the study was to determine whether NGF influences the production of VEGF by hGCs and to identify a potential signaling pathway underlying this effect. Design: We conducted a prospective experimental study. Patients: hGCs were obtained from 41 women participating in the in vitro fertilization program of our institution. Methods: Changes in VEGF mRNA after exposure to NGF were evaluated in cultured hGCs by PCR and real-time PCR. The effect of NGF on VEGF secretion was determined by ELISA. The involvement of trkA, the high affinity NGF receptor, was examined by inhibiting the receptor's tyrosine kinase activity with K252a. The contribution of an ERK1/ERK2-mediated signaling pathway was identified by detecting NGF-dependent phosphorylation of these proteins and by blocking their activity with the inhibitor U0126. Results: NGF promotes VEGF production in cultured hGCs. Blockade of trkA receptor tyrosine kinase activity blocks this effect. NGF induces MAPK-ERK2 phosphorylation, and blockade of this signaling pathway prevents the NGF-induced increase in VEGF production. Conclusions: NGF promotes ovarian angiogenesis by enhancing the synthesis and secretion of VEGF from hGCs via a trkA- and ERK2-dependent mechanism.

    Original languageEnglish (US)
    Pages (from-to)3065-3071
    Number of pages7
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume94
    Issue number8
    DOIs
    StatePublished - Aug 2009

    Fingerprint

    trkA Receptor
    Granulosa Cells
    Nerve Growth Factor
    Mitogen-Activated Protein Kinases
    Vascular Endothelial Growth Factor A
    Phosphotransferases
    Phosphorylation
    Vascular Endothelial Growth Factors
    Nerve Growth Factor Receptor
    Ovarian Follicle
    Angiogenesis Inducing Agents
    Receptor Protein-Tyrosine Kinases
    Fertilization in Vitro
    Protein-Tyrosine Kinases
    Mental Competency
    Blood Vessels
    Real-Time Polymerase Chain Reaction

    ASJC Scopus subject areas

    • Biochemistry
    • Clinical Biochemistry
    • Endocrinology
    • Biochemistry, medical
    • Endocrinology, Diabetes and Metabolism

    Cite this

    Nerve growth factor induces vascular endothelial growth factor expression in granulosa cells via a trkA receptor/mitogen-activated protein kinase-extracellularly regulated kinase 2-dependent pathway. / Julio-Pieper, Marcela; Lozada, Patricia; Tapia, Veronica; Vega, Margarita; Miranda, Cristián; Vantman, David; Ojeda, Sergio; Romero, Carmen.

    In: Journal of Clinical Endocrinology and Metabolism, Vol. 94, No. 8, 08.2009, p. 3065-3071.

    Research output: Contribution to journalArticle

    Julio-Pieper, Marcela ; Lozada, Patricia ; Tapia, Veronica ; Vega, Margarita ; Miranda, Cristián ; Vantman, David ; Ojeda, Sergio ; Romero, Carmen. / Nerve growth factor induces vascular endothelial growth factor expression in granulosa cells via a trkA receptor/mitogen-activated protein kinase-extracellularly regulated kinase 2-dependent pathway. In: Journal of Clinical Endocrinology and Metabolism. 2009 ; Vol. 94, No. 8. pp. 3065-3071.
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    abstract = "Context: Acquisition of ovulatory competence by antral follicles requires development of an adequate vascular supply. Although it is well established that ovarian angiogenesis is cyclically regulated by vascular endothelial growth factor (VEGF), the factors controlling VEGF production by ovarian follicles remain largely unknown. Nerve growth factor (NGF) may be one of these factors, because NGF promotes angiogenesis and synthesis of angiogenic factors in other tissues and is produced by human granulosa cells (hGCs). Objective: The aim of the study was to determine whether NGF influences the production of VEGF by hGCs and to identify a potential signaling pathway underlying this effect. Design: We conducted a prospective experimental study. Patients: hGCs were obtained from 41 women participating in the in vitro fertilization program of our institution. Methods: Changes in VEGF mRNA after exposure to NGF were evaluated in cultured hGCs by PCR and real-time PCR. The effect of NGF on VEGF secretion was determined by ELISA. The involvement of trkA, the high affinity NGF receptor, was examined by inhibiting the receptor's tyrosine kinase activity with K252a. The contribution of an ERK1/ERK2-mediated signaling pathway was identified by detecting NGF-dependent phosphorylation of these proteins and by blocking their activity with the inhibitor U0126. Results: NGF promotes VEGF production in cultured hGCs. Blockade of trkA receptor tyrosine kinase activity blocks this effect. NGF induces MAPK-ERK2 phosphorylation, and blockade of this signaling pathway prevents the NGF-induced increase in VEGF production. Conclusions: NGF promotes ovarian angiogenesis by enhancing the synthesis and secretion of VEGF from hGCs via a trkA- and ERK2-dependent mechanism.",
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    T1 - Nerve growth factor induces vascular endothelial growth factor expression in granulosa cells via a trkA receptor/mitogen-activated protein kinase-extracellularly regulated kinase 2-dependent pathway

    AU - Julio-Pieper, Marcela

    AU - Lozada, Patricia

    AU - Tapia, Veronica

    AU - Vega, Margarita

    AU - Miranda, Cristián

    AU - Vantman, David

    AU - Ojeda, Sergio

    AU - Romero, Carmen

    PY - 2009/8

    Y1 - 2009/8

    N2 - Context: Acquisition of ovulatory competence by antral follicles requires development of an adequate vascular supply. Although it is well established that ovarian angiogenesis is cyclically regulated by vascular endothelial growth factor (VEGF), the factors controlling VEGF production by ovarian follicles remain largely unknown. Nerve growth factor (NGF) may be one of these factors, because NGF promotes angiogenesis and synthesis of angiogenic factors in other tissues and is produced by human granulosa cells (hGCs). Objective: The aim of the study was to determine whether NGF influences the production of VEGF by hGCs and to identify a potential signaling pathway underlying this effect. Design: We conducted a prospective experimental study. Patients: hGCs were obtained from 41 women participating in the in vitro fertilization program of our institution. Methods: Changes in VEGF mRNA after exposure to NGF were evaluated in cultured hGCs by PCR and real-time PCR. The effect of NGF on VEGF secretion was determined by ELISA. The involvement of trkA, the high affinity NGF receptor, was examined by inhibiting the receptor's tyrosine kinase activity with K252a. The contribution of an ERK1/ERK2-mediated signaling pathway was identified by detecting NGF-dependent phosphorylation of these proteins and by blocking their activity with the inhibitor U0126. Results: NGF promotes VEGF production in cultured hGCs. Blockade of trkA receptor tyrosine kinase activity blocks this effect. NGF induces MAPK-ERK2 phosphorylation, and blockade of this signaling pathway prevents the NGF-induced increase in VEGF production. Conclusions: NGF promotes ovarian angiogenesis by enhancing the synthesis and secretion of VEGF from hGCs via a trkA- and ERK2-dependent mechanism.

    AB - Context: Acquisition of ovulatory competence by antral follicles requires development of an adequate vascular supply. Although it is well established that ovarian angiogenesis is cyclically regulated by vascular endothelial growth factor (VEGF), the factors controlling VEGF production by ovarian follicles remain largely unknown. Nerve growth factor (NGF) may be one of these factors, because NGF promotes angiogenesis and synthesis of angiogenic factors in other tissues and is produced by human granulosa cells (hGCs). Objective: The aim of the study was to determine whether NGF influences the production of VEGF by hGCs and to identify a potential signaling pathway underlying this effect. Design: We conducted a prospective experimental study. Patients: hGCs were obtained from 41 women participating in the in vitro fertilization program of our institution. Methods: Changes in VEGF mRNA after exposure to NGF were evaluated in cultured hGCs by PCR and real-time PCR. The effect of NGF on VEGF secretion was determined by ELISA. The involvement of trkA, the high affinity NGF receptor, was examined by inhibiting the receptor's tyrosine kinase activity with K252a. The contribution of an ERK1/ERK2-mediated signaling pathway was identified by detecting NGF-dependent phosphorylation of these proteins and by blocking their activity with the inhibitor U0126. Results: NGF promotes VEGF production in cultured hGCs. Blockade of trkA receptor tyrosine kinase activity blocks this effect. NGF induces MAPK-ERK2 phosphorylation, and blockade of this signaling pathway prevents the NGF-induced increase in VEGF production. Conclusions: NGF promotes ovarian angiogenesis by enhancing the synthesis and secretion of VEGF from hGCs via a trkA- and ERK2-dependent mechanism.

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