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(Investigative Ophthalmology and Visual Science. 2003;44:4994-5005.)
© 2003 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.03-0291
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FGF-2 Antagonizes the TGF-ß1-Mediated Induction of Pericyte {alpha}-Smooth Muscle Actin Expression: A Role for Myf-5 and Smad-Mediated Signaling Pathways

Michael Papetti, Jaleel Shujath, Kathleen N. Riley, and Ira M. Herman

From the Program in Cellular and Molecular Physiology, Department of Physiology, Tufts University School of Medicine, Boston, Massachusetts.

PURPOSE. Although the FGF and TGF-ß families are known to play an important role in regulating vascular endothelial and smooth muscle cell behavior, the influence of these matrix-binding growth factors on microvascular pericyte morphogenesis is not well understood. The current study was undertaken to examine the molecular mechanisms that mediate the effects of the endothelium-produced growth regulators FGF-2 and TGF-ß1 on retinal pericyte proliferation and contractile phenotype.

METHODS. Using purified retinal pericytes, a series of assays were implemented, including RT-PCR, DNA binding, immunoprecipitation, electrophoretic mobility shift, and indirect immunofluorescence, in an attempt to elucidate the FGF/TGF-ß1 signaling cascades that mediate retinal microvascular cell growth and contractile phenotype.

RESULTS. Treatment of retinal pericytes with FGF-2 and heparin stimulated nearly a log order increase in proliferation, whereas removal of FGF-2 or addition of TGF-ß1 caused withdrawal from the growth cycle, inducing a smooth-muscle-like contractile phenotype, as indicated by upregulation of {alpha}-smooth muscle actin ({alpha}-SMA). This switch from a growth-potentiated to a growth-arrested state followed induction of the transcriptional regulator myf-5, as well as the nuclear translocation of myf-5 and Smad2.

CONCLUSIONS. Several critical features of the endothelial cell-extracellular matrix-pericyte molecular signaling axis were elucidated in the study that are likely to be responsible for regulating retinal microvascular morphogenesis during normal development, as well as the pathologic angiogenesis accompanying several ocular disorders, including diabetic retinopathy and age-related macular degeneration.




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