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J Thorac Cardiovasc Surg 2009;138:163-171
© 2009 The American Association for Thoracic Surgery

Evolving Technology/Basic Science

Signal transducer and activator of transcription 3–stimulated hypoxia inducible factor-1{alpha} mediates estrogen receptor-{alpha}–induced mesenchymal stem cell vascular endothelial growth factor production

Meijing Wang, MDb, Jiangning Tan, MD, PhDb, Arthur Coffey, MDa, John Fehrenbacher, MDa, Brent R. Weil, MDb, Daniel R. Meldrum, MDa,b,c,*

a Clarian Cardiovascular Surgery, Methodist Hospital, Indianapolis, Ind
b Department of Surgery, Indiana University School of Medicine, Indianapolis, Ind
c Department of Physiology, Indiana University School of Medicine, Indianapolis, Ind

Received for publication October 31, 2008; revisions received February 25, 2009; accepted for publication March 11, 2009.

* Address for reprints: Daniel R. Meldrum, MD, 635 Barnhill Drive MS 2001, Indianapolis, IN 46202. (Email: dmeldrum{at}iupui.edu).

Objective: Vascular endothelial growth factor, a critical factor in angiogenesis, mediates stem cell paracrine protective effects on ischemic myocardium. Studies on the role of sex in stem cell function have demonstrated that female mesenchymal stem cells produce greater vascular endothelial growth factor and provide better cardiac protection compared with male mesenchymal stem cells. The purpose of this study was to determine the mechanisms by which estrogen affects mesenchymal stem cell function as a potential therapeutic measure during ex vivo expansion, before therapeutic use.

Methods: A single-step purification method using adhesion to cell culture plastic was adopted to isolate mesenchymal stem cells from wild-type, estrogen receptor-{alpha} knockout, estrogen receptor-β knockout, and signal transducer and activator of transcription 3 knockout mice. Mesenchymal stem cells were treated with or without 17β-estradiol, estrogen receptor-{alpha} agonist (propyl pyrazoletriol), and estrogen receptor-β agonist (diarylpropionitrile).

Results: 17β-estradiol significantly increased mesenchymal stem cell vascular endothelial growth factor production in a dose-dependent manner. Both estrogen receptor-{alpha} and estrogen receptor-β were expressed in mesenchymal stem cells. Administration of 17β-estradiol or estrogen receptor-{alpha} agonist (not estrogen receptor-β agonist) elevated mesenchymal stem cell vascular endothelial growth factor, hypoxia inducible factor-1{alpha} expression, and signal transducer and activator of transcription 3 activation. However, these effects were neutralized in estrogen receptor-{alpha} knockout mesenchymal stem cells, not estrogen receptor-β knockout. Signal transducer and activator of transcription 3 knockout abolished estrogen receptor-{alpha}–induced hypoxia inducible factor-1{alpha} and subsequent vascular endothelial growth factor production.

Conclusion: 17β-estradiol–induced vascular endothelial growth factor production from mesenchymal stem cells appears to be mediated through estrogen receptor-{alpha}–activated signal transducer and activator of transcription 3-mediated hypoxia inducible factor-1{alpha} expression.

Abbreviations and Acronyms E2 = 17β-estradiol; ELISA = enzyme-linked immunosorbent assay; ER = estrogen receptor; DPN = diarylpropiolnitrile; HIF = hypoxia-inducible factor; KO = knockout; MAPK = mitogen-activated protein kinase; MSC = mesenchymal stem cell; PPT = propyl pyrazoletriol; STAT3 = signal transducer and activator of transcription-3; VEGF = vascular endothelial growth factor; WT = wild type






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