Complement Factor B Mediates Ocular Angiogenesis through Regulating the VEGF Signaling Pathway.

Hannah Murray,Sze Yuan Ho,Xiaomeng Wang,Beiying Qiu

doi:10.3390/ijms22179580

Abstract

Complement factor B (CFB), a 95-kDa protein, is a crucial catalytic element of the alternative pathway (AP) of complement. After binding of CFB to C3b, activation of the AP depends on the proteolytic cleavage of CFB by factor D to generate the C3 convertase (C3bBb). The C3 convertase contains the catalytic subunit of CFB (Bb), the enzymatic site for the cleavage of a new molecule of C3 into C3b. In addition to its role in activating the AP, CFB has been implicated in pathological ocular neovascularization, a common feature of several blinding eye diseases, however, with somewhat conflicting results. The focus of this study was to investigate the direct impact of CFB on ocular neovascularization in a tightly controlled environment. Using mouse models of laser-induced choroidal neovascularization (CNV) and oxygen-induced retinopathy (OIR), our study demonstrated an increase in CFB expression during pathological angiogenesis. Results from several in vitro and ex vivo functionality assays indicated a promoting effect of CFB in angiogenesis. Mechanistically, CFB exerts this pro-angiogenic effect by mediating the vascular endothelial growth factor (VEGF) signaling pathway. In summary, we demonstrate compelling evidence for the role of CFB in driving ocular angiogenesis in a VEGF-dependent manner. This work provides a framework for a more in-depth exploration of CFB-mediated effects in ocular angiogenesis in the future.

Highlights

Angiogenesis refers to the growth of new blood vessels from pre-existing vasculature [1]
Our study showed a steady increase in Cfb expression as the retinal vasculature develops from P2 to P21 (Figure 1a)
We showed that Cfb expression was significantly attenuated in the hyperoxic retina at P11 as compared to that in the normoxic retina (Figure 1b) which mirrors the expression of the well-characterized angiogenic factor, Vegf (Figure 1c)

Summary

Introduction

Angiogenesis refers to the growth of new blood vessels from pre-existing vasculature [1]. During this process, endothelial cells (EC) will first branch out from a parent vessel by proliferation and migration, extending into the surrounding matrix [2]. Endothelial cells (EC) will first branch out from a parent vessel by proliferation and migration, extending into the surrounding matrix [2] Perivascular cells, such as smooth muscle cells and pericytes, will subsequently be recruited to the nascent vessels, which secrete extracellular matrix (ECM) proteins and provide further support to newly formed blood vessels [3,4,5]. Over the last two decades, pharmacological agents targeting VEGF have transformed the treatment landscape for ocular angiogenic diseases

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