Liver regeneration is a salivary VEGF dependent phenomenon

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Introduction: Liver “regeneration” following partial hepatectomy (PH) is associated with VEGF upregulation and involves the formation of a complex network of liver sinusoids through which the blood flows. Previous work in our lab demonstrates the importance of submandibular salivary gland- derived VEGF in small bowel adaptation following massive small bowel resection. We hypothesize that salivary- derived VEGF may be essential to the regenerative stimulus for the compensatory growth after PH. We examined the effect on liver regeneration following PH, of both submandibular gland excision (SAL) and selective blockade of VEGF by Ad-VEGF-trap with and without supplemental Oro-gastric VEGF replacement. Methods: C57BL/6 Male mice underwent either Sham operation (n=5), PH alone (70% liver resection, n=5), PH+SAL (n=5), PH+AdVEGF-trap (1× 108 pfu) via retrograde parotid duct injection (n=4), PH+SAL+VEGF (100ng/ml) (n=5). Animals were harvested after 14 days. Liver regeneration was evaluated by wet liver weights. Hepatic angiogenesis was quantified by intrahepatic microvascualr density using CD31 (PECAM-1) staining of paraffin embedded liver. Statistical analysis was performed with ANOVA. Results: The wet liver weight was significantly lower in SAL treated mice compared to control PH mice (0.996±0.26gms vs.1.2±0.31gms, p=0.005) as it was in selective blockade of VEGF treated mice (1.00±0.48gms vs.1.2±0.31gms,p=0.005). Compared to the PH group microvascualr density was significantly reduced in the SAL (46.04±3.31 vs.59.8±2.32,p=0.005) and selective VEGF blockade (43.6±1.07 vs.59.8±2.32,p=0.005).VEGF supplementation in the PH+SAL+ VEGF group normalized both wet liver weight (1.15±0.46gms vs. 1.2±0.31gms p=ns) and the microvascualr density (59.80±2.32 vs.62.97±2.38,p=ns). Conclusion: Liver regeneration is a salivary VEGF dependent process. SAL and selective blockade of VEGF with Ad VEGF-trap block hepatic regeneration based on wet weight and microvascualr density. Oral VEGF supplementation completely corrects the liver regeneration and vessel density, demonstrating a previously unrecognized role of salivary VEGF in inducing neovascularization dependent liver regeneration. These results may suggest new therapeutic strategies to augment compensatory growth of liver following resection.