Vascular endothelial cells not only respond to secreted signals but also generate signals that direct development and regeneration. Angiopoietin-2 (Ang2) is a vascular growth factor that is produced by endothelial cells during angiogenesis and inflammation. Unexpectedly, Hu et al. found that Ang2 expression decreased in liver sinusoidal endothelial cells (LSECs) 1 day after partial hepatectomy compared to its expression in LSECs from sham-operated mice. Ang2 mRNA abundance then gradually increased and was comparable to Ang2 mRNA abundance in control livers after the regenerated liver had regained its preoperative mass and vasculature 8 days after surgery. Hepatocyte proliferation and liver mass peaked 4 days after hepatectomy in livers from wild-type (WT) mice but peaked 2 days after hepatectomy in Ang2–/– mice, suggesting that LSEC-derived Ang2 repressed hepatocyte proliferation. Whereas hepatocyte growth factor (HGF) stimulated several mitogenic signaling pathways and DNA synthesis in primary cultured WT hepatocytes, Ang2 did not activate these pathways and did not promote DNA synthesis. Ang2 and its receptor Tie2 were present only in LSECs, implying that Ang2 did not repress hepatocyte proliferation directly but rather acted in an autocrine manner in LSECs to control the production of another signal that regulated hepatocyte proliferation. Indeed, Ang2 production in LSECs correlated with secretion of transforming growth factor–β1 (TGFβ1), which repressed hepatocyte proliferation by inducing cell cycle arrest. TGFβ1 expression was reduced in LSECs and liver lysates from Ang2–/– mice and hepatectomized mice, respectively, compared with control tissues. Cell culture and in vitro experiments were consistent with this reduction in TGFβ1 removing a proliferation block in hepatocytes during the early phase of regeneration. In the later angiogenic phase of regeneration, the recovery of Ang2 signaling promoted proliferation of LSECs by stimulating their expression of vascular endothelial growth factor receptor 2 (VEGFR2). Therefore, this study demonstrated that temporal regulation of Ang2 expression is key to enabling hepatocyte proliferation and revascularization of new liver tissue after injury. Under normal conditions, Ang2-dependent production of TGFβ1 in LSECs represses hepatocyte proliferation. Liver injury causes LSECs to rapidly reduce Ang2 expression, thus allowing hepatocytes to proliferate to replace the lost tissue. LSECs gradually restore Ang2 production, which stimulates their proliferation to form the vasculature for the regenerated organ.
J. Hu, K. Srivastava, M. Wieland, A. Runge, C. Mogler, E. Besemfelder, D. Terhardt, M. J. Vogel, L. Cao, C. Korn, S. Bartels, M. Thomas, H. G. Augustin, Endothelial cell–derived Angiopoietin-2 controls liver regeneration as a spatiotemporal rheostat. Science 343, 416–419 (2014). [Abstract] [Full Text]