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

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.

Endothelial VEGFR Coreceptors Neuropilin-1 and Neuropilin-2 Are Essential for Tumor Angiogenesis

“…Given both NRP1 and NRP2 are known to modulate primary and secondary tumor microenvironments by interacting with integrins to remodel the tumoral ECM ( 20, 64, 66 ), of which FN is known as a major component ( 67 ), it follows that the impaired tumor growth exhibited following NRP codepletion likely arises as a result of perturbations in EDA-FN fibril assembly and deposition. Indeed, EDA-FN has been demonstrated to facilitate tumor growth and invasiveness by promoting matrix stiffness, sustaining tumor-induced angiogenesis and lymphangiogenesis via VEGF-A 165 ( 68 ) and VEGF-C, respectively ( 69 ). For example, Su and colleagues , revealed that EDA-FN secretion promoted VEGFR-2 recruitment to β1 integrin sites, upregulating VEGFR-2 phosphorylation and pathologic angiogenesis during hepatic fibrosis in a CD63-dependent manner ( 68 ).…”

“…Indeed, EDA-FN has been demonstrated to facilitate tumor growth and invasiveness by promoting matrix stiffness, sustaining tumor-induced angiogenesis and lymphangiogenesis via VEGF-A 165 ( 68 ) and VEGF-C, respectively ( 69 ). For example, Su and colleagues , revealed that EDA-FN secretion promoted VEGFR-2 recruitment to β1 integrin sites, upregulating VEGFR-2 phosphorylation and pathologic angiogenesis during hepatic fibrosis in a CD63-dependent manner ( 68 ).…”

Endothelial neuropilin-1 and neuropilin-2 are essential for tumour angiogenesis

“…Given both NRP1 and NRP2 are known to modulate primary and secondary tumour microenvironments by interacting with integrins to remodel the tumoral ECM [20], [45], [47], of which FN is known as a major component [48], it follows that the impaired tumour growth exhibited following NRP co-depletion likely arises as a result of perturbations in EDA-FN fibril assembly and deposition. Indeed, EDA-FN has been demonstrated to facilitate tumour growth and invasiveness by promoting matrix stiffness, sustaining tumour-induced angiogenesis and lymphangiogenesis via VEGF-A 165 [49] and VEGF-C respectively [50]. For example, Su et al ., revealed that EDA-FN secretion promoted VEGFR-2 recruitment to β1 integrin sites, upregulating VEGFR-2 phosphorylation and pathological angiogenesis during hepatic fibrosis in a CD63-dependent manner [49].…”

“…Indeed, EDA-FN has been demonstrated to facilitate tumour growth and invasiveness by promoting matrix stiffness, sustaining tumour-induced angiogenesis and lymphangiogenesis via VEGF-A 165 [49] and VEGF-C respectively [50]. For example, Su et al ., revealed that EDA-FN secretion promoted VEGFR-2 recruitment to β1 integrin sites, upregulating VEGFR-2 phosphorylation and pathological angiogenesis during hepatic fibrosis in a CD63-dependent manner [49].…”

A Meta-Analysis of Human Transcriptomics Data in the Context of Peritoneal Dialysis Identifies Novel Receptor-Ligand Interactions as Potential Therapeutic Targets

“…In mesothelial cells we found a 3.7-fold upregulation, which is associated with fibrosis in PD patients. KDR was also found to be involved in CKD in general as well as in other indications such as liver disease [36][37][38]. SEMA6D is part of the semaphorin protein family that can act as ligand as well as receptor via reverse signaling [39,40].…”