Regulation of cell proliferation by HB-EGF in mouse cardiac valve development

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HB-EGF, a member of the EGF family of growth factors, plays an important role in cardiac valve development by suppressing mesenchymal cell proliferation. In this study, we reveal that HB-EGF must interact with heparan sulfate proteoglycans (HSPGs) to properly function in this process. Further study to elucidate the molecular mechanism involved in HB-EGF-mediated suppression of cell proliferation suggests that EGFR and the downstream JNK- and p38MAPK-signaling cascades in mesenchymal cells are involved in the growth inhibition. Moreover, EGFR-signaling is also involved in the up-regulation of cell proliferation when HB-EGF is deleted in developing valves, suggesting that the opposite signaling cascades of HB-EGF/EGFR-mediated growth-inhibition and the other EGFR-ligand(s)/EGFR-mediated growth promotion are competing in normal cardiac valve development.