Abstract
Although administration of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, could improve the overall survival of destroyed sinusoidal endothelial cells (SEC) in chemically induced murine acute hepatic failure (AHF), the mechanistic roles of the VEGF receptors have not been elucidated yet. The respective roles of VEGF receptors; namely, Flt-1 (VEGFR-1: R1) and KDR/Flk-1 (VEGFR-2: R2), in the D-galactosamine (Gal-N) and lipopolysaccharide (LPS)-induced AHF were elucidated with specific neutralizing monoclonal antibody against R1 and R2 (R1-mAb and R2-mAb, respectively). The serum ALT elevation, with a peak at 24 h after Gal-N+LPS intoxication, was markedly augmented by means of the R1-mAb and R2-mAb. The aggregative effect of R2-mAb was more potent than that of R1-mAb, and the survival rate was 70% in the R2-mAb-treated group and 100% in the other groups. The results of SEC destruction were almost parallel to those of the ALT changes. Our in-vitro study showed that R1-mAb and R2-mAb significantly worsened the Gal-N+LPS-induced cytotoxicity and apoptosis of SEC mediated by caspase-3, which were almost of similar magnitude to those in the in-vivo study. In conclusion, these results indicated that R2 is a major regulator of the salvage effect of VEGF on the maintenance of SEC architecture and the anti-apoptotic effects against chemically-induced murine AHF.
Highlights
Despite the recent advances in liver support systems, acute hepatic failure (AHF) still has a high mortality rate [ 1].Among several types of non-parenchymal cells, the sinusoidal endothelial cells (SEC) are considered the most important in the recovery from AHF [ 2]
It has been shown that the vascular endothelial growth factor (VEGF) expression increased markedly during liver regeneration induced either by partial hepatectomy (PH)
In addition to the vitality of regeneration, we previously reported that the VEGF-mediated maintenance of the SEC architecture through anti-apoptotic effects in AHF is important
Summary
Among several types of non-parenchymal cells, the sinusoidal endothelial cells (SEC) are considered the most important in the recovery from AHF [ 2]. Several studies have proven that neovascularization requires these processes during the recovery from AHF [ 4]. Emerging evidences have shown that angiogenesis plays a pivotal role in many physiological and pathological processes, such as tumor growth, arthritis, psoriasis, and diabetic retinopathy [ 5, 7]. The vascular endothelial growth factor (VEGF) is the most potent factor in the angiogenesis process [ 8]. Emerging evidences have shown that VEGF plays a pivotal role in many processes of physiological and pathological angiogenesis [ 9]. VEGF is an angiogenic factor and known as a survival factor for EC [ 10]. It has been shown that the VEGF expression increased markedly during liver regeneration induced either by partial hepatectomy (PH)
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