Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells.

Fernando S. Mesquita, Summer N. Dyer, Daniel A. Heinrich, Serdar E. Bulun, Erica E. Marsh, Romana A. Nowak

Research output: Contribution to journalArticle

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Abstract

Uterine leiomyomas are benign uterine tumors characterized by extracellular matrix remodeling, increased collagen deposition, and increased smooth muscle cell (SMC) proliferation. The reactive oxygen species (ROS) producing NADPH oxidase complex has been shown to be involved in the signaling pathways of several growth factors, cytokines, and vasoactive agents that stimulate proliferation of a variety of cell types. Our objective was to test the hypothesis that ROS derived from NADPH oxidase is a necessary component of the MAP kinase mitogenic pathway activated by platelet derived growth factor (PDGF) and epidermal growth factor (EGF) in leiomyoma SMCs (LSMCs). Primary cell cultures of LSMCs were used as our experimental model. Our results showed that stimulation of these cells with PDGF or EGF caused a marked increase in intracellular ROS production and that the NADPH oxidase inhibitor, DPI, blocks ROS production. In addition, inhibition of ROS production by NADPH oxidase inhibitors blocked, in a dose-dependent manner, the EGF- and PDGF-induced increase in [(3)H]thymidine incorporation by LSMCs. Furthermore, an exogenous source of ROS, hydrogen peroxide, was sufficient to stimulate [(3)H]thymidine incorporation in LSMCs but did not affect COL1A2 and COL3A1 mRNA levels. Inhibition of the NADPH oxidase complex decreased PDGF-induced MAPK1/MAPK3 activation, whereas exogenous hydrogen peroxide induced MAPK1/MAPK3 activation. This article is the first report suggesting the presence of the NADPH oxidase system and its importance in mitogenic signaling pathways in LSMCs. The necessity of NADPH oxidase-derived ROS for EGF and PDGF signaling pathways leading to cell proliferation points to another potential therapeutic target for treatment and/or prevention of uterine leiomyomas.

Original languageEnglish (US)
Pages (from-to)341-351
Number of pages11
JournalBiology of reproduction
Volume82
Issue number2
DOIs
StatePublished - Feb 2010

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NADPH Oxidase
Leiomyoma
Smooth Muscle Myocytes
Reactive Oxygen Species
Intercellular Signaling Peptides and Proteins
Platelet-Derived Growth Factor
Epidermal Growth Factor
Thymidine
Hydrogen Peroxide
Cell Proliferation
Primary Cell Culture
Extracellular Matrix
Theoretical Models
Phosphotransferases
Collagen
Cytokines
Messenger RNA
Neoplasms

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Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. / Mesquita, Fernando S.; Dyer, Summer N.; Heinrich, Daniel A.; Bulun, Serdar E.; Marsh, Erica E.; Nowak, Romana A.

In: Biology of reproduction, Vol. 82, No. 2, 02.2010, p. 341-351.

Research output: Contribution to journalArticle

Mesquita, Fernando S. ; Dyer, Summer N. ; Heinrich, Daniel A. ; Bulun, Serdar E. ; Marsh, Erica E. ; Nowak, Romana A. / Reactive oxygen species mediate mitogenic growth factor signaling pathways in human leiomyoma smooth muscle cells. In: Biology of reproduction. 2010 ; Vol. 82, No. 2. pp. 341-351.
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