Abstract
We examined the effects of VEGFA on damage and regeneration in steatotic and non-steatotic livers of rats submitted to PH under I/R, and characterized the underlying mechanisms involved. Our results indicated that VEGFA levels were decreased in both steatotic and non-steatotic livers after surgery. The administration of VEGFA increased VEGFA levels in non-steatotic livers, reducing the incidence of post-operative complications following surgery through the VEGFR2-Wnt2 pathway, independently of Id1. Unexpectedly, administration of VEGFA notably reduced VEGFA levels in steatotic livers, exacerbating damage and regenerative failure. After exogenous administration of VEGFA in steatotic animals, circulating VEGFA is sequestered by the high circulating levels of sFlt1 released from adipose tissue. Under such conditions, VEGFA cannot reach the steatotic liver to exert its effects. Consequently, the concomitant administration of VEGFA and an antibody against sFlt1 was required to avoid binding of sFlt1 to VEGFA. This was associated with high VEGFA levels in steatotic livers and protection against damage and regenerative failure, plus improvement in the survival rate via up-regulation of PI3K/Akt independently of the Id1-Wnt2 pathway. The current study highlights the different effects and signaling pathways of VEGFA in liver surgery requiring PH and I/R based in the presence of steatosis.Key messagesVEGFA administration improves PH+I/R injury only in non-steatotic livers of Ln animals.VEGFA benefits are exerted through the VEGFR2-Wnt2 pathway in non-steatotic livers.In Ob rats, exogenous VEGFA is sequestered by circulating sFlt1, exacerbating liver damage.Therapeutic combination of VEGFA and anti-sFlt1 is required to protect steatotic livers.VEGFA+anti-sFlt1 treatment protects steatotic livers through a VEGFR2-PI3K/Akt pathway.
Highlights
In clinical situations, partial hepatectomy (PH) under ischemia/reperfusion (I/R) is a common strategy to control bleeding during parenchymal dissection [1]
PH+I/R+vascular endothelial growth factor A (VEGFA) in non-steatotic livers exhibited higher VEGFA immunohistochemical staining in both hepatocytes and in nonparenchymal cells than that found in the PH+I/R group (Fig. 1B)
VEGFA administration (PH+I/R+VEGFA group) protected against hepatic damage as indicated by the reduced transaminases, GLDH, damage score values, and the extent and number of necrotic areas in non-steatotic livers when compared with the PH+I/R group (Fig. 1C)
Summary
Partial hepatectomy (PH) under ischemia/reperfusion (I/R) is a common strategy to control bleeding during parenchymal dissection [1]. A number of experimental studies on PH without I/R in steatotic and non-steatotic livers have shown that vascular endothelial growth factor A (VEGFA) levels are increased after surgery and that infusion of VEGFA can reduce injury and increase hepatocyte proliferation [6,7,8,9]. Protective effects on damage have been reported regarding the role of VEGFA in non-steatotic livers in experimental models of I/R without PH [10, 11]. It has been shown that in non-steatotic livers undergoing PH without I/R, VEGFR2 activation is induced, initiating Id1 up-regulation and secretion of Wnt angiocrine factor [7]. Recent studies have suggested an important role of Wnt signaling in the proliferative response in non-steatotic livers undergoing I/R without PH [18]
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