Pharmacological inhibition of integrin αvβ3 aggravates experimental liver fibrosis and suppresses hepatic angiogenesis

Abstract

The vitronectin receptor integrin ␣v␤3 promotes angiogenesis by mediating migration and proliferation of endothelial cells, but also drives fibrogenic activation of hepatic stellate cells (HSCs) in vitro. Expecting antifibrotic synergism, we studied the effect of ␣v␤3 inhibition in two in vivo models of liver fibrogenesis. Liver fibrosis was induced in rats by way of bile duct ligation (BDL) for 6 weeks or thioacetamide (TAA) injections for 12 weeks. A specific ␣v␤3 (␣v␤5) inhibitor (Cilengitide) was given intraperitoneally twice daily at 15 mg/kg during BDL or after TAA administration. Liver collagen was determined as hydroxyproline, and gene expression was quantified by way of quantitative polymerase chain reaction. Liver angiogenesis, macrophage infiltration, and hypoxia were assessed by way of CD31, CD68 and hypoxia-inducible factor-1␣ immunostaining. Cilengitide decreased overall vessel formation. This was significant in portal areas of BDL and septal areas of TAA fibrotic rats and was associated with a significant increase of liver collagen by 31% (BDL) and 27% (TAA), and up-regulation of profibrogenic genes and matrix metalloproteinase-13. Treatment increased gamma glutamyl transpeptidase in both models, while other serum markers remained unchanged.

Loss of myeloid cell-derived vascular endothelial growth factor accelerates fibrosis

“…It further argues that diminished angiogenesis is directly causative of aggravated fibrosis of the lung. Finally, our findings are in agreement with observations from other organs like the kidney and liver, where inhibition of angiogenesis and subsequent hypoxia promoted fibrosis (41,42). Fibrotic lungs from animals lacking VEGF in myeloid cells show elevated levels of nuclear β-catenin and cyclin D1, a major downstream component of the Wnt/β-catenin signaling pathway (27), indicating increased Wnt/β-catenin signaling.…”

Aquaporin-1 Promotes Angiogenesis, Fibrosis, and Portal Hypertension Through Mechanisms Dependent on Osmotically Sensitive MicroRNAs

“…Indeed, most strategies targeting angiogenic molecules have shown benefit in preclinical animal models of liver disease. 11,[31][32][33][34] In this context, our study extends the current knowledge of an emerging anti-angiogenic target, AQP1, by providing direct in vivo evidence that AQP1 regulates the angiogenesis, fibrosis, and portal hypertension that occurs after BDL; and defining a novel, molecular, fine-tuning mechanism involving osmotically sensitive miRs that may contribute to the pathological overexpression of AQP1 during cirrhosis. We previously demonstrated that AQP1 is overexpressed in the angiogenic neovasculature within fibrotic septa in human cirrhosis and in CCl 4 -induced liver injury in C57 black mice.…”

Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis

“…Hepatic hydroxyproline (HYP) was measured as described previously (27,28). Briefly, liver tissues (200 mg) were hydrolyzed in 6 mol/L HCl at 110°C for 16 h. Fifty microliters of each sample was incubated with chloramine T (2.5 mmol/L) for 5 min and Ehrlich's reagent (410 mmol/L) for 30 min at 60°C.…”