Role of vascular endothelial growth factor in the pathophysiology of nonalcoholic steatohepatitis in two rodent models

Abstract

The pathophysiology of nonalcoholic steatohepatitis (NASH) should be approached as a multifactorial process. In several stages of NASH, a link between disease progression and hepatic microvasculature changes can be made. In this study we investigated the role of angiogenesis in two mouse models for NASH, and the effect of a preventive and therapeutic antiangiogenic treatment in a diet-induced mouse model for NASH. Protein and RNA levels of angiogenic and inflammatory factors were significantly up-regulated in the liver of C56BL/6 and db/db mice with NASH at different timepoints. To examine the effect of angiogenic factors on the disease progression of NASH, a prevention and treatment study was set up, blocking the placental growth factor (PlGF) or vascular endothelial growth factor receptor 2 (VEGFR2). Our study showed that treatment prevents the progression of NASH by attenuating steatosis and inflammation, both in a preventive and therapeutic setting, thereby confirming the hypothesis that angiogenic factors play an early role in the disease progression from steatosis to NASH. Anti-PlGF (aPlGF) did not significantly improve liver histology. Vascular corrosion casting showed a more disrupted liver vasculature in mice with NASH compared to controls. Treatment with aVEGFR2 showed an improvement of the liver vasculature. Moreover, fat-laden primary hepatocytes treated with aVEGFR2 stored significantly less lipids. Conclusion: Our results demonstrate that there is an increased expression of angiogenic factors in the liver in different mouse models for NASH. We found that VEGFR2 blockage attenuates steatosis and inflammation in a diet-induced mouse model for NASH in a preventive and therapeutic setting. Our findings warrant further investigation of the role of angiogenesis in the pathophysiology in NASH.

Development of an in vitro human liver system for interrogating nonalcoholic steatohepatitis

“…Over the tested time course, several proinflammatory cytokines increased, including IL-8, IL-6, and CXCL10, all of which have established chemoattractant properties and are upregulated in NAFL/NASH patients or mouse models ( Figure 5D) (26,27). Studies have found that angiogenic factors, such as VEGF, are increased and contribute to the progression of NASH in animal models (28). In agreement, we found levels of VEGF to be increased at day 5.…”

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

“…For instance, CCL2-dependent infiltrating macrophages derived from BM into the injured liver facilitate angiogenesis during the evolution of liver fibrosis through releasing pro-angiogenic factors including VEGF [43]. Additionally, inflammatory hepatic macrophages are involved in angiogenesis with enhancement of VEGF in the progression of nonalcoholic steatohepatitis [44]. Thus, recruited macrophages are likely main mediators of sinusoidal reconstitution and hepatic angiogenesis both in acute and chronic liver injury.…”

Origins of Portal Hypertension in Nonalcoholic Fatty Liver Disease

“…There is increasing evidence that neovascularization is a key element in the progression of NAFLD [56,57]. Formation of new blood vessels in chronic liver disease is linked to the advancement of fibrosis, indicating a close interplay between LSECs and HSCs.…”

“…Vascular endothelial growth factor (VEGF) is the master regulator of this process, mediating both pro-fibrogenic and pro-angiogenic signals and supported by HIF activation in hypoxic areas [57]. Importantly, serum VEGF levels of patients with steatosis and steatohepatitis are higher compared to healthy controls [56]. Moreover, in animal models of genetic (db/db) and methionine-choline-deficient diet (MCDD)-induced NAFLD, increased VEGF levels occur as early as 3 days into steatosis before steatohepatitis of fibrosis develops [56].…”

“…Importantly, serum VEGF levels of patients with steatosis and steatohepatitis are higher compared to healthy controls [56]. Moreover, in animal models of genetic (db/db) and methionine-choline-deficient diet (MCDD)-induced NAFLD, increased VEGF levels occur as early as 3 days into steatosis before steatohepatitis of fibrosis develops [56]. Intralobular arterioles occasionally drain to sinusoids midway between zones 1 and 3 in the classic liver lobule [58].…”