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Review
. 2024 Jul 1;4(5):452-466.
doi: 10.1515/mr-2023-0048. eCollection 2024 Oct.

Complement factor H in molecular regulation of angiogenesis

Jiang Li  1   2   3 , Kaili Wang  1   2 , Maria N Starodubtseva  4   5 , Eldar Nadyrov  4 , Carolyn M Kapron  6 , Josephine Hoh  7 , Ju Liu  1   2   4
Affiliations
Review

Complement factor H in molecular regulation of angiogenesis

Jiang Li et al. Med Rev (2021). .

Abstract

Angiogenesis, the process of formation of new capillaries from existing blood vessels, is required for multiple physiological and pathological processes. Complement factor H (CFH) is a plasma protein that inhibits the alternative pathway of the complement system. Loss of CFH enhances the alternative pathway and increases complement activation fragments with pro-angiogenic capacity, including complement 3a, complement 5a, and membrane attack complex. CFH protein contains binding sites for C-reactive protein, malondialdehyde, and endothelial heparan sulfates. Dysfunction of CFH prevents its interaction with these molecules and initiates pro-angiogenic events. Mutations in the CFH gene have been found in patients with age-related macular degeneration characterized by choroidal neovascularization. The Cfh-deficient mice show an increase in angiogenesis, which is decreased by administration of recombinant CFH protein. In this review, we summarize the molecular mechanisms of the anti-angiogenic effects of CFH and the regulatory mechanisms of CFH expression. The therapeutic potential of recombinant CFH protein in angiogenesis-related diseases has also been discussed.

Keywords: angiogenesis; complement factor H; mechanical properties; therapeutic target.

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Conflict of interest statement

Competing interests: Authors declare no conflict of interest.

Figures

Figure 1:
Figure 1:
Structure of CFH protein. (A) The image of the best-fit model of CFH in 137 mM NaCl was generated using Visual Molecular Dynamics (VMD) (University of Illinois at Urbana-Champaign). The short consensus repeats (SCRs) are numbered from 1 to 20 to indicate the positions of the SCR domains. (B) Major binding sites for C3b, CRP, GAG and MDA were highlighted in red. CFH, complement factor H; CRP, C-reactive protein; GAG, glycosaminoglycan; MDA, malondialdehyde.
Figure 2:
Figure 2:
The function of CFH in alternative pathway of the complement system. The alternative pathway C3 convertase (C3bBb) cleavage C3, which leads to release bioactive fragments, C3a and C3b. The generation of C3b form more C3bBb with Bb, resulting in positive feedback. C3bBb binding C3b also form C5 convertase to cleavage C5, which leads to the common terminal pathway, and finally produces the lytic membrane attack complex (MAC). CFH inhibits the alternative pathway by inactivating C3b, reducing the formation of C3 convertase and accelerating decay of the formed C3 convertase and C5 convertase. C3a, C5a and MAC contribute to endothelial cell migration and proliferation to promote angiogenesis. Thus, CFH decreases the generation of three pro-angiogenic effectors, C3a, C5a and MAC, to inhibit angiogenesis. CFH, complement factor H; CFI, complement factor I.
Figure 3:
Figure 3:
Schematic cartoon of wet AMD in the presence of CFH variants. (A) CFH variants related to AMD were highlighted. The protein structure was predicted by AlphaFold (DeepMind). (B) CFH variants promote proangiogenic events. The left panel is the physiological condition in the presence of CFH. The right panel is wet AMD under dysfunction of CFH. Blood vessels extend from the choroidal vessel into the subretinal space beneath the photoreceptors through the damaged Bruch’s membrane and retinal pigment epithelium. CFH, complement factor H; AMD, age-related macular degeneration.
Figure 4:
Figure 4:
The potential effects of CFH on HS and the stiffness of ECs. CFH may bind HS structures and CFH-HS complexes reduce the binding of VEGF and bFGF to their receptors. Loss of CFH may increase of stiffness of cytoskeleton and shear stress induced NO, which increase EC migration and permeability. CFH, complement factor H; OxLDL, oxidized low-density lipoprotein; VEGF, vascular endothelial growth factor; bFGF, basic fibroblast growth factor; HSPG, heparan sulfate proteoglycan; VEGFR2, vascular endothelial growth factor receptor 2; FGFR1, fibroblast growth factor receptor 1; NO, nitric oxide; HS, heparan sulfate; EC, endothelial cell.
Figure 5:
Figure 5:
Regulatory mechanism of CFH expression. (A) Upregulation of CFH expression. VEGF stimulates phosphorylation of CREB by PKC-α to increase CFH expression. Cadmium activates the −1635 AP-1 binding element on the CFH promoter. IFN-γ stimulates the nuclear translocation of STAT1, leading to up-regulation of CFH expression mediated by IRF-1 and IRF-8. (B) Downregulation of CFH expression. Oxidative stress induces acetylation of FOXO3 which binds competitively to the CFH promoter, to suppress CFH expression. The miRNAs (miRNA-9, miRNA-125b, miRNA-146a, and miRNA-155) bind to CFH mRNA and induce its degradation. IFN-γ, interferon-gamma; VEGF, vascular endothelial growth factor; JAK1, Janus kinase 1; JAK2, Janus kinase 2; STAT1, signal transducer and activator of transcription 1; JNK, c-Jun N-terminal kinase; PKC-α, protein kinase C alpha; CREB, cAMP response element binding protein; IRF-1, interferon regulatory factor-1; IRF-8, interferon regulatory factor-8; FOXO3, forkhead box transcription factor O3; AP-1, activator protein-1; miRNA, microRNA.
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