Angiogenesis in liver regeneration and fibrosis: “a double-edged sword”

Abstract

Angiogenesis, defined as the formation of new microvasculature from preexisting blood vessels and mature endothelial cells, plays a major role in wound healing and scar formation, and it is associated with inflammatory responses. Angiogenesis can occur in physiological conditions, such as during liver regeneration, and in pathological situations, such as during the progression of fibrosis to cirrhosis and also during tumor angiogenesis. Cellular cross-talk among liver sinusoidal endothelial cells (LSECs), hepatic stellate cells and hepatocytes is believed to play an important role in the angiogenesis process during both liver regeneration and development of cirrhosis. In addition to mature endothelial cells, bone marrow (BM)-derived circulating endothelial progenitor cells (EPCs) have been recently identified for their contribution to post-natal vasculogenesis/angiogenesis. In vivo, EPCs are mobilized into the peripheral blood in response to tissue ischemia or traumatic injury, migrate to the sites of injured endothelium and differentiate into mature endothelial cells. In our recent studies, we have explored the role of EPC-mediated angiogenesis in liver regeneration and/or cirrhosis. Results have demonstrated significantly increased endogenous levels of circulating EPCs in cirrhotic patients in comparison to the controls. Also, EPCs from cirrhotic patients have been observed to stimulate substantial angiogenesis by resident LSECs in vitro via paracrine factors such as vascular endothelial growth factor and platelet-derived growth factor. This review gives an overview of the angiogenesis process in liver regeneration and disease and discusses a new mechanism for intrahepatic angiogenesis mediated by BM-derived EPCs.

Hypoxic‐ischemic gene expression profile in the isolated variant of biliary atresia

“…Decreased VEGFA-VEGFR2 expression in BA could have a protective role, since modulation of these molecules is a proposed treatment for liver diseases [52], but recent studies have shown that blocking VEGFA expression aggravates liver fibrosis [53][54][55]. The decreased VEGFA and VEFGR2 gene expression observed in BA in the present study may not imply a protective role; conversely, it seems to be associated with worsening disease [56].…”

Cytokines, hepatic cell profiling and cell interactions during bone marrow cell therapy for liver fibrosis in cholestatic mice

“…Even a small increase in the number of endothelial cells during fibrosis, as observed in our results after cell therapy, could have an important role in tissue remodeling. However, these cells are also associated with tissue tumorigenesis and metastasis, and it is noteworthy that only when healthy animals were injected with BMC, endothelial progenitor cells percentage was highly increased, suggesting that the safety of BMC transplantation is associated with the presence of a chronic liver injury in our model [ 25 , 26 ].…”

Role of thrombospondin 1 in liver diseases

“…Hepatic angiogenesis is closely related to fibrosis in both clinical and experimental conditions . The cross‐talk among hepatic sinusoidal endothelial cells, stellate cells, and hepatocytes plays an important role in the angiogenesis process during liver regeneration and fibrosis development . Studies showed that pathological angiogenesis and sinusoidal remodeling may act as the initiators of liver fibrosis and the angiogenesis pathway has been targeted for treatment of liver fibrosis .…”