FN-EDA mediates angiogenesis of hepatic fibrosis via integrin-VEGFR2 in a CD63 synergetic manner

Xiaonan Su,Chenxi Liu,Hao Wu,Jianni Qi,Zhen Yu,Xiaoyu Xie,Yuemin Feng,Xiaowen Ma,Qiang Zhu,Le Wang

doi:10.1038/s41420-020-00378-9

Abstract

Pathological angiogenesis is an important component of hepatic fibrosis along with fibrous deposition, but its role is not well understood. Here, we demonstrated that fibronectin containing extra domain A(FN-EDA), a fibronectin splice variant highly expressed in hepatic fibrosis, mediated angiogenesis in disease progression. FN-EDA was positively correlated with pathological angiogenesis in hepatic fibrosis, and a reduction in FN-EDA expression was associated with diminished intrahepatic angiogenesis and fibrosis. FN-EDA mostly colocalized with hepatic stellate cells (HSCs) and interference or blockage of FN-EDA attenuated migration and tube formation in co-cultured endothelial cells. Mechanistic studies indicated that FN-EDA was secreted to promote phosphorylation of VEGFR2 with the assistance of integrin and CD63. Targeting FN-EDA-integrin combination postponed the progression of hepatic angiogenesis and fibrosis in vivo. These results indicated that FN-EDA plays an emerging role in angiogenesis in hepatic fibrosis and could be a potential therapeutic intervention for the disease.

Highlights

Hepatic fibrosis is a successive process that is accompanied by excessive deposition of extracellular matrixes (ECM) and pathological angiogenesis, which is frequently observed in patients with chronic liver diseases[1]
In this study, we focused on FN-EDA, a special splicing variant of fibronectin, and provided evidence to clarify its role in pathological angiogenesis and the cross-talk between hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells (HSECs) in hepatic fibrosis
We observed that FN-EDA itself could promote the phosphorylation of VEGFR2, and further demonstrated the promotion effect occurred through integrin receptors and was CD63 dependent (Fig. 7)

Summary

Introduction

Hepatic fibrosis is a successive process that is accompanied by excessive deposition of extracellular matrixes (ECM) and pathological angiogenesis, which is frequently observed in patients with chronic liver diseases[1]. Increasing evidence have indicated that intrahepatic pathological angiogenesis with an aberrant angioarchitecture is an indispensable part of hepatic fibrogenesis[3,4]. Pathological angiogenesis triggered by vascular endothelial growth factor (VEGF) overproduction is believed to be central to liver fibrosis progress and the development of portal hypertension[5,6,7]. FN-EDA and FN-EDB are expressed nearly ubiquitously in embryonic tissues and are associated with cardiovascular development[16,17,18] while their expressions are strictly limited in normal adult tissues but is increased in various pathological states. Accumulated evidence has demonstrated that FN-EDA participates in some fibrotic diseases of many organs, including the dermis, lung and bone marrow[19,20,21], and several physiopathologic

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Conclusion