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 language | English (US) |
|---|---|
| Pages (from-to) | 3065-3071 |
| Number of pages | 7 |
| Journal | Journal of Clinical Endocrinology and Metabolism |
| Volume | 94 |
| Issue number | 8 |
| DOIs | |
| State | Published - Aug 2009 |
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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 journal › Article
}
TY - JOUR
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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UR - http://www.scopus.com/inward/citedby.url?scp=68549096011&partnerID=8YFLogxK
U2 - 10.1210/jc.2009-0542
DO - 10.1210/jc.2009-0542
M3 - Article
C2 - 19454577
AN - SCOPUS:68549096011
VL - 94
SP - 3065
EP - 3071
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
SN - 0021-972X
IS - 8
ER -