Inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration

Abstract

Angiogenesis occurs through a convergence of diverse signaling mechanisms with prominent pathways that include autocrine effects of endothelial nitric oxide (NO) synthase (eNOS)-derived NO and vascular endothelial growth factor (VEGF). However, the redundant and distinct roles of NO and VEGF in angiogenesis remain incompletely defined. Here, we use the partial hepatectomy model in mice genetically deficient in eNOS to ascertain the influence of eNOS-derived NO on the angiogenesis that accompanies liver regeneration. While sinusoidal endothelial cell (SEC) eNOS promotes angiogenesis in vitro, surprisingly the absence of eNOS did not influence the angiogenesis that occurs after partial hepatectomy in vivo. While this observation could not be attributed to induction of alternate NOS isoforms, it was associated with induction of VEGF signaling as evidenced by enhanced levels of VEGF ligand in regenerating livers from mice genetically deficient in eNOS. However, surprisingly, mice that were genetically heterozygous for deficiency in the VEGF receptor, fetal liver kinase-1, also maintained unimpaired capacity for liver regeneration. In summary, inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration, indicating signaling redundancies that allow liver regeneration to continue in the absence of this canonical vascular pathway.

Endothelial nitric oxide synthase is a key mediator of hepatocyte proliferation in response to partial hepatectomy in mice

“…We did not observe any compensatory increase in iNOS protein or mRNA expression in eNOS −/− livers subjected to PH. Our studies confirm previous observations that the iNOS isoform does not compensate for eNOS deficiency in regenerating livers 25. Despite distinct impairments in hepatocyte proliferation, liver growth at 8 days post‐PH was comparable between WT and eNOS −/− livers.…”

“…Several recent studies suggest that eNOS is expressed in hepatocytes, in addition to endothelial cells, in the liver 6‐10. However, previous studies with eNOS −/− mice have led to conflicting findings on its potential roles in hepatocyte proliferation in response to PH 10, 25. Recently, Vasquez‐Chantada et al described a role for LKB1‐AMPK in HGF‐induced eNOS phosphorylation in hepatocytes and impaired BrdU incorporation in response to PH in eNOS −/− , as compared to WT 10.…”

Adenosine A2Breceptor stimulates angiogenesis by inducing VEGF and eNOS in human microvascular endothelial cells

“…16 Moreover, AR have attracted attention for their contribution to angiogenesis. However, the underlying mechanism regarding the modulation of AR on the secretion of VEGF and NO remain unrevealed.…”

Microarchitecture of the liver: A Jigsaw puzzle

“…However, there are other factors that could play a role in organizing the microarchitecture of the liver. These include among others, the induction of endothelial cell proliferation by VEGF or NO [6,7], the production of Wingless (Wnt) and hedgehog (Hh) ligands by hepatocytes and liver sinusoidal cells [8], and the secretion of TGF-b, a negative regulator of hepatocyte proliferation [1]. In addition, EM produced could play a key role in harboring growth factors (i.e.…”

“…What is the role of VEGF in sustaining sinusoidal endothelial cells? Shergill et al [6] showed that in a mouse model of liver regeneration post-hepatectomy, inhibition of VEGF and NOdependent angiogenesis did not impair liver regeneration. However, in a model of regeneration post-acetaminophen toxicity, Donahower et al [7] showed that the administration of recombinant VEGF reduced necrosis and enhanced hepatocyte regeneration.…”