Liver regeneration requires spatially and temporally precisely coordinated proliferation of the different cellular compartments of the liver, most notably hepatocytes and liver sinusoidal endothelial cells (LSEC), to reconstitute liver structure and physiological function.The mechanisms involved in the coordination of liver regeneration remain elusive.We found that the expression of Angiopoietin-2 (Ang2) in LSEC is temporally regulated following partial hepatectomy.Ang2 thereby controls liver regeneration through paracrine hepatotropic and autocrine endotheliotropic mechanisms.During the early inductive phase of liver regeneration,Ang2 downregulation leads to reduced LSEC TGFβ1 production, thereby enabling hepatocyte proliferation by releasing an angiocrine proliferative brake.During the later angiogenic phase of liver regeneration, recovery of endothelial Ang2 expression restores the angiocrine inhibition of hepatocyte proliferation and enables regenerative angiogenesis by controlling LSEC VEGFR-2 expression.The data establish LSEC as dynamic rheostat of liver regeneration spatiotemporally orchestrating hepatocytes and LSEC proliferation through Angiopoietin-2 and shed light on promoting liver regeneration by manipulating LSEC.