VEGFR1-Positive Macrophages Facilitate Liver Repair and Sinusoidal Reconstruction after Hepatic Ischemia/Reperfusion Injury

Abstract

Liver repair after acute liver injury is characterized by hepatocyte proliferation, removal of necrotic tissue, and restoration of hepatocellular and hepatic microvascular architecture. Macrophage recruitment is essential for liver tissue repair and recovery from injury; however, the underlying mechanisms are unclear. Signaling through vascular endothelial growth factor receptor 1 (VEGFR1) is suggested to play a role in macrophage migration and angiogenesis. The aim of the present study was to examine the role of VEGFR1 in liver repair and sinusoidal reconstruction after hepatic ischemia/reperfusion (I/R). VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK-/- mice) and wild-type (WT) mice were subjected to hepatic warm I/R, and the processes of liver repair and sinusoidal reconstruction were examined. Compared with WT mice, VEGFR1 TK-/- mice exhibited delayed liver repair after hepatic I/R. VEGFR1-expressing macrophages recruited to the injured liver showed reduced expression of epidermal growth factor (EGF). VEGFR1 TK-/- mice also showed evidence of sustained sinusoidal functional and structural damage, and reduced expression of pro-angiogenic factors. Treatment of VEGFR1 TK-/- mice with EGF attenuated hepatoceullar and sinusoidal injury during hepatic I/R. VEGFR1 TK-/- bone marrow (BM) chimeric mice showed impaired liver repair and sinusoidal reconstruction, and reduced recruitment of VEGFR1-expressing macrophages to the injured liver. VEGFR1-macrophages recruited to the liver during hepatic I/R contribute to liver repair and sinusoidal reconstruction. VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury.

Exogenous vascular endothelial growth factor delivery prior to endothelial precursor cell transplantation in orthotopic liver transplantation–induced hepatic ischemia/reperfusion injury

“…Moreover, VEGF's binding to LSECs also triggers the release of HB‐EGF through an overlapping VEGFR‐1/2–based mechanism . Although VEGF has not been shown to directly up‐regulate EGF transcript expression through either VEGFR‐1 or VEGFR‐2, VEGFR‐1–expressing macrophages secrete EGF and increasing VEGFR‐1 signaling has been shown to up‐regulate EGF expression in VEGF‐stimulated macrophages . Consistent with this evidence, we observed that VEGF gene delivery prior to EPC transplantation was able to increase the expression of all 4 hepatotrophic factors (ie, EGF, HB‐EGF, HGF, and TGF‐α) in post‐OLT–induced HIRI.…”

“…Following liver injury, both hepatocytes and HSCs have been shown to quickly up‐regulate their VEGF secretion in response to cytokines as well as hypoxia in order to support hepatic recovery . VEGF acts on its target cells via 2 key tyrosine kinase receptors named VEGFR‐1 (alternatively fms related tyrosine kinase 1 [Flt‐1]) and VEGFR2 (alternatively fetal liver kinase‐1 [Flk‐1] and kinase insert domain receptor [KDR]) . Because increased VEGF expression has been shown to be linked to both VEGFR‐1 up‐regulation on hepatocytes as well as VEGFR‐1 and VEGFR‐2 up‐regulation on LSECs, here we successfully confirmed the effective liposomal delivery of the VEGF gene to the target liver tissue of the VEGF‐treated groups.…”

“…VEGF has been well established as an angiogenic factor, as it promotes endothelial cell proliferation as well as the expression of various proteases that enable new blood vessel formation . As VEGFR‐2 activation by VEGF promotes LSEC proliferation, normal VEGF‐induced angiogenesis is held to be mediated by VEGFR‐2, whereas VEGFR‐1 activation can lead to dysfunctional angiogenesis . Moreover, VEGFR‐2 activation (as opposed to VEGFR‐1 activation) by VEGF has been shown to up‐regulate the proangiogenic NO‐producing enzymes eNOS and iNOS .…”

VEGF 165 b Modulates Endothelial VEGFR1–STAT3 Signaling Pathway and Angiogenesis in Human and Experimental Peripheral Arterial Disease

“…Several of the VEGFR1 functions that have been identified are in non-ECs (33,34,35,36,37,38) , and endothelial specific VEGFR1 functions remain uncertain. Our experimental data showed that VEGF 165 b-inhibition induces VEGFR1-activation not VEGFR2 or its downstream signaling in Balb/c ischemic muscle.…”

Lysophosphatidic Acid Alters the Expression Profiles of Angiogenic Factors, Cytokines, and Chemokines in Mouse Liver Sinusoidal Endothelial Cells

“…By using VEGFR1 tyrosine kinase knockout mice, Ohkubo H et al found that VEGFR1-expressing macrophages were recruited to the liver during hepatic ischemia/reperfusion and contribute to liver repair and sinusoidal reconstruction through regulating expression of pro-angiogenic factors. This study demonstrated that VEGFR1 activation is a potential therapeutic strategy for promoting liver repair and sinusoidal restoration after acute liver injury [ 22 ]. Coulon S et al demonstrated that the blockage of VEGFR2 could attenuate steatosis and inflammation in a diet-induced mouse model for nonalcoholic steatohepatitis.…”