Boosting the hypoxic response in myeloid cells accelerates resolution of fibrosis and regeneration of the liver in mice

Abstract

We have recently shown that targeting Vascular Endothelial Growth Factor (VEGF) specifically in scar-infiltrating myeloid cells prevented remodeling of the sinusoidal vasculature and abrogated the resolution of murine liver fibrosis, thereby unmasking an unanticipated link between angiogenesis and resolution of fibrosis. In a gain of function approach, we wanted to test the impact of VEGF overexpression in myeloid cells on fibrolysis. We observe that genetic inactivation of the von Hippel Lindau protein (VHL), a negative regulator of Hypoxia-inducible factors (HIF) in myeloid cells, leads to increased VEGF expression and most importantly, accelerated matrix degradation and reduced myofibroblast numbers after CCl4 challenge. This is associated with enhanced expression of MMP-2 and -14 as well as lower expression of TIMP-2 in liver endothelial cells. In addition, we report increased expression of MMP-13 in scar-associated macrophages as well as improved liver regeneration upon ablation of VHL in myeloid cells. Finally, therapeutic infusion of macrophages nulli-zygous for VHL or treated with the pharmacologic hydroxylase inhibitor and HIF-inducer Dimethyloxalylglycine (DMOG) accelerates resolution of fibrosis. Hence, boosting the HIF-VEGF signaling axis in macrophages represents a promising therapeutic avenue for the treatment of liver fibrosis.

The Endothelium as a Driver of Liver Fibrosis and Regeneration

“…VEGF increases significantly during fibrosis resolution, produced by LSEC and myeloid cells [158]. VEGF fosters a LSEC pro-resolution phenotype with increased expression of MMP-2 and MMP-4, reduced expression of TIMP-1 and TIMP-2 and increased MMP-13 expression in macrophages [158,249], altogether promoting hepatic scar vascularization and fibrosis resolution. Importantly, fibrolytic properties have been attributed to LSEC that following VEGF overexpression are able to accelerate matrix degradation and improve liver regeneration [249].…”

“…VEGF fosters a LSEC pro-resolution phenotype with increased expression of MMP-2 and MMP-4, reduced expression of TIMP-1 and TIMP-2 and increased MMP-13 expression in macrophages [158,249], altogether promoting hepatic scar vascularization and fibrosis resolution. Importantly, fibrolytic properties have been attributed to LSEC that following VEGF overexpression are able to accelerate matrix degradation and improve liver regeneration [249]. Therefore VEGF may have a dual role in fibrosis; it is essential in maintaining LSEC physiological phenotype through NO regulation [250] during fibrosis onset and promote reversion of HSC activated phenotype, ameliorating LSEC dysfunction during fibrosis resolution [12].…”

Expression of Matrix Metalloproteinase-2, Tissue Inhibitor of Matrix Metalloproteinase-2 and CD147 in the Traditional Chinese Medicine “Compound T11” for Treatment of Chronic Liver Injury

“…CD147 is an important factor in MMP-2 activation [8]. If the expression of MMP-2 and CD147 can be increased and TIMP-2 expression can be reduced, ECM degradation can be promoted and liver fibrosis reversed [18,19].…”

Molecular factors associated with regression of liver fibrosis of alcoholic etiology

“…Так, у особей с деплецией гена VEGF наблюдалось персистирование фиброгенеза даже после прекращения повреждающего действия CCl4, а введение данного фактора способствовало деградации внеклеточного матрикса [26]. VEGF-опосредованный фибролизис обусловлен повышением уровня секреции MMP2 и 14 эндотелиальными клетками печени, а также индукцией экспрессии MMP7, 9 и 13 [27].…”