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Fig. 5 a Flow cytometric analysis of the liver nonparenchymal cells. VEGFR2 + cells that are
CD45 - , express endothelial-specific VE-cadherin. b Specific expression of VEGFR3 on
VEGFR2 + VE-cadherin + CD45 - LSECs, with a predominant fraction being CD34 - Factor-
VIII + Prox-1 - . c Forty-eight hours after partial hepatectomy, E-cadherin + P-H3 + mitotic hepato-
cytes are localized adjacent to VE-cadherin + and VEGFR2 + endothelial cells. Scale bars, 50 lm
(Adapted from [ 65 ])
deficient, VEGFR2 flox/flox (VEGFR2 fl/fl ) mice [ 68 ]. Owing to the endothelial-cell
specific expression of VEGFR2 in the liver, in VEGFR2 fl/fl mice only liver ECs,
but not non-endothelial cells, will manifest functional defects. As control, we used
mice with heterozygous deletion of the VEGFR2 gene (VEGFR2 fl/+ ). Forty-eight
hours after partial hepatectomy, bromodeoxyuridine + hepatocyte proliferation
(BrdU + HNF4A + cell number) was decreased by 67 % in VEGFR2 fl/fl mice
(Fig. 7 a, b). Despite the patency of the VE-cadherin + isolectin + perfused vessels at
this early phase, the regeneration of liver mass was attenuated in VEGFR2 fl/fl mice
(Fig. 7 c). The result demonstrates that in the early phases (PH days 1-3) of liver
regeneration, targeting VEGFR2 primarily impairs the effect of endothelial-
derived angiocrine factors to induce hepatocyte regeneration, but not vascular
perfusion capacity.
However, in VEGFR2 fl/fl mice at the later stages of liver regeneration (PH days
4-8), proliferative angiogenesis was also defective (Fig. 7 c), interfering with the
assembly of patent VE-cadherin + isolectin + vasculature (Fig. 7 d, e), thereby
diminishing restoration of the liver mass for at least 28 days. Furthermore, in
VEGFR2 fl/fl mice, liver function after PH was abnormal, as manifested by elevated
plasma bilirubin levels. To confirm the endothelial-specific VEGFR2 function
in mediating liver regeneration, VEGFR2 loxP/loxP mice were also crossed with
VE-cadherin-CreER T2 mice to induce endothelial-selective deletion of VEGFR2.
Both the liver mass and formation of perfused vessels in the VE-cadherin-
CreER T2 VEGFR2 fl/fl mice were decreased after PH, which emphasizes the sig-
nificance of VEGFR2 in mediating liver regeneration. In fact, if the VEGF-A/
VEGFR2 pathway supports SEC-driven hepatic regeneration, then VEGF-A
should enhance liver regeneration. We compared the effect of VEGF-A 164 with
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