Interplay Between Macrophages and Angiogenesis: A Double-Edged Sword in Liver Disease

Abstract

During chronic liver disease, macrophages support angiogenesis, not only by secreting proangiogenic growth factors and matrix-remodeling proteases, but also by physically interacting with the sprouting vasculature to assist the formation of complex vascular networks. In the liver, macrophages acquire specific characteristics becoming Kupffer cells and working to ensure protection and immunotolerance. Angiogenesis is another double-edged sword in health and disease and it is the biggest ally of macrophages allowing its dissemination. Angiogenesis and fibrosis may occur in parallel in several tissues as macrophages co-localize with newly formed vessels and secrete cytokines, interleukins, and growth factors that will activate other cell types in the liver such as hepatic stellate cells and liver sinusoidal endothelial cells, promoting extracellular matrix accumulation and fibrogenesis. Vascular endothelial growth factor, placental growth factor, and platelet-derived growth factor are the leading secreted factors driving pathological angiogenesis and consequently increasing macrophage infiltration. Tumor development in the liver has been widely linked to macrophage-mediated chronic inflammation in which epidermal growth factors, STAT3 and NF-kβ are some of the most relevant signaling molecules involved. In this article, we review the link between macrophages and angiogenesis at molecular and cellular levels in chronic liver disease.

Effect of Hepatic Macrophage Polarization and Apoptosis on Liver Ischemia and Reperfusion Injury During Liver Transplantation

“…Under steady-state conditions, KCs have close contact with circulating blood flowing from the portal vein or hepatic artery, which allows them to devour most pathogens. In addition, they are responsible for removing other substances, including cell debris and immune complexes ( 13 ). It is now believed that KCs in healthy livers exhibit a “tolerogenic” phenotype that can maintain immune tolerance.…”

Crosstalk Between Liver Macrophages and Surrounding Cells in Nonalcoholic Steatohepatitis

“…Besides, those activated macrophages further mediate the activation of hepatic stellate cells (HSCs) via producing cytokines and chemokines, including transforming growth factor-β (TGFβ), interleukin-1β (IL-1β), platelet-derived growth factor (PDGF) receptor, and CC-chemokine ligand 2 (CCL2) (10). Moreover, liver macrophages influence the biological functions of liver sinusoidal endothelial cells (LSECs) and other immune cells (11,12). In turn, those surrounding cells can stimulate liver macrophages during NASH progression (13,14).…”

Involvement of lncRNAs and Macrophages: Potential Regulatory Link to Angiogenesis

“…By now, although the activation of the downstream pathway during angiogenesis is still not completely clear, activated macrophages could influence the angiogenic process through the production of angiogenic factors such as IL-1, IL-6, IL-8, TNF-α, TGF-α, TGF-β, GM-CSF, bFGF, and VEGF [68]. Moreover, activation of NF-κB and STAT3 is involved in the upstream pathway of macrophageinduced angiogenesis [69,70]. Thus, macrophages and angiogenesis are very closely linked with complicated mechanisms.…”