Objectives: To investigate the effects of estrogen on growth and smooth muscle cell (SMC)-differentiation of vascular wall-resident CD34(+) stem/progenitor cells (VRS/Pcs).
Methods and results: The existence of CD34(+) VRS/Pcs was confirmed by immunohistochemistry in the adventitia of arteries of young (2-month-old) and old (24-month-old) female SD rats with less CD34(+) adventitial cells detected in the old. The VRS/Pcs isolated from young animals were grown in Stem cell growth medium or induced to differentiate into SMC with PDGF-BB in the presence or absence of 17β-estrodiol (E2). Flow cytometry, RT-qPCR and Western blot showed that E2 promoted Brdu incorporation of the CD34(+) VRS/Pcs growing in Stem cell growth medium; but when the cells were incubated in PDGF-BB, the hormone enhanced their expression of SMC marker SM22. ChIP and IP assays showed that E2 significantly promoted the binding of pELK1-SRF complex to the promoter of c-fos gene in CD34(+) VRS/Pcs growing in the Stem cell growth medium; but when the cells were stimulated with PDGF-BB, an E2-enhanced binding of myocardin-SRF to the promoter of SM22 gene was found with enhanced expression of SRC3 and its binding to myocardin. The effects of E2 above could be blocked by the estrogen receptor antagonist ICI 182,780 or inhibited by SRF-siRNA.
Conclusion: Estrogen has dual effects on CD34(+) VRS/Pcs. For the undifferentiated VRS/Pcs, it accelerates their proliferation by enhancing binding of pELK1-SRF complex to c-fos gene; while for the differentiating VRS/Pcs, it promotes their differentiation to SMC through a mechanism of SRC3-mediated interaction of myocardin-SRF complex with SM22 gene.
Keywords: Differentiation; Estrogen; Proliferation; Vascular wall-resident stem/progenitor cells.
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