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Vitreous humor proteome: unraveling the molecular mechanisms underlying proliferative and neovascular vitreoretinal diseases

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Abstract

Proliferative diabetic retinopathy (PDR), proliferative vitreoretinopathy (PVR), and neovascular age-related macular degeneration (nAMD) are among the leading causes of blindness. Due to the multifactorial nature of these vitreoretinal diseases, omics approaches are essential for a deeper understanding of the pathophysiologic processes underlying the evolution to a proliferative or neovascular etiology, in which patients suffer from an abrupt loss of vision. For many years, it was thought that the function of the vitreous was merely structural, supporting and protecting the surrounding ocular tissues. Proteomics studies proved that vitreous is more complex and biologically active than initially thought, and its changes reflect the physiological and pathological state of the eye. The vitreous is the scenario of a complex interplay between inflammation, fibrosis, oxidative stress, neurodegeneration, and extracellular matrix remodeling. Vitreous proteome not only reflects the pathological events that occur in the retina, but the changes in the vitreous itself play a central role in the onset and progression of vitreoretinal diseases. Therefore, this review offers an overview of the studies on the vitreous proteome that could help to elucidate some of the pathological mechanisms underlying proliferative and/or neovascular vitreoretinal diseases and to find new potential pharmaceutical targets.

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Data availability

The data reviewed in this paper is available in the original papers from proteomics and multiplex studies. These revised papers include the references [43,44,45,46,47,48, 52, 54, 59, 60, 62,63,64, 68,69,70,71, 98] for DR/PDR, [63, 93, 156, 157] for AMD, and [46, 188,189,190,191,192,193,194,195, 256] for RRD/PVR. The reviewed data is displayed in the supplementary table.

Abbreviations

2DE:

Two-dimensional electrophoresis

AAT:

Alpha-1-antitrypsin

AGEs:

Advanced glycation end products

AMD:

Age-related macular degeneration

Ang-1:

Angiopoietin 1

Ang-2:

Angiopoietin-2

APP:

Amyloid-beta A4 protein

BDNF:

Brain-derived neurotrophic factor

BRB:

Blood-retinal barrier

C3:

Complement C3

CA:

Carbonic anhydrase

CCN2:

Connective tissue growth factor

CE–MS:

Capillary electrophoresis coupled to mass spectrometry

CFH:

Complement factor H

CLU:

Clusterin

CNTF:

Ciliary neurotrophic factor

CNV:

Choroidal neovascularization

CSF3:

Granulocyte colony-stimulating factor

CXCL10:

C-X-C motif chemokine 10

DME:

Diabetic macular edema

DR:

Diabetic retinopathy

ECM:

Extracellular matrix

EMT:

Epithelial-mesenchymal transition

ENO2:

Gamma-enolase

ERM:

Epiretinal membranes

FGF:

Fibroblast growth factor

GDNF:

Glial cell-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

HIF-1:

Hypoxia-inducible factor

ICAM-1:

Intercellular adhesion molecule 1

IGFBPs:

Insulin-like growth factor-binding proteins

IGFs:

Insulin-like growth factors

IL1-β:

Interleukin-1 beta

IL-6:

Interleukin-6

IL-8:

Interleukin-8

IL-10:

Nterleukin-10

INF-γ:

Interferon-gamma

KKS:

Kallikrein-Kinin system

LC–MS:

Liquid chromatography coupled to mass spectrometry

MCP-1:

Monocyte chemoattractant protein-1

MMP9:

Matrix metalloproteinase 9

MMP2:

72 KDa type IV collagenase

MMPs:

Metalloproteinases

MNV:

Macular neovascularization

nAMD:

“Wet” or neovascular age-related macular degeneration

NGF:

Nerve growth factor

NT3:

Neurotrophin-3

NV:

Neovascularization

PDGF:

Platelet-derived growth factor

PDR:

Proliferative diabetic retinopathy

PECAM-1:

Platelet endothelial cell adhesion molecule

PEDF:

Pigment epithelium-derived factor

PlGF:

Placental growth factor

PVD:

Posterior vitreous detachment

PVR:

Proliferative vitreoretinopathy

RD:

Retinal detachment

ROS:

Reactive oxygen species

RPE:

Retinal pigment epithelium

RRD:

Rhegmatogenous retinal detachment

SRF:

Subretinal fluid

TGF-β:

Transforming growth factor

Tie-2:

Tyrosine kinase receptor

TIMP-1:

Metalloproteinase inhibitor 1

TIMP2:

Metalloproteinase inhibitor 2

TNF-α:

Tumor necrosis factor

TTR:

Transthyretin

VCAM-1:

Vascular cell adhesion protein-1

VEGF:

Vascular endothelial growth factor

VEGFR-1:

Vascular endothelial growth factor receptor 1

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Acknowledgements

Fátima Millhano Santos acknowledges a doctoral fellowship [SFRH/BD/112526/2015] from the Portuguese Foundation for Science and Technology (FCT). This work was developed within the scope of the CICS-UBI projects UIDB/00709/2020 and UIDP/00709/2020, financed by national funds through the FCT/MCTES. It was also funded by the European Regional Development Fund through the “Programa Operacional Regional do Centro (Centro 2020)—Sistema de Apoio à Investigação Científica e Tecnológica—Programas Integrados de IC&DT”, Centro-01-0145-FEDER-000019-C4-Centro de Competências em Cloud Computing. CNB-CSIC proteomics lab is a member of Proteored, PRB3-ISCIII, supported by grant PT17/0019/0001. CNB-CSIC has been designated Centre of Excellence “Severo Ochoa” and is funded by the Spanish Government through Grant SEV2017-0712. This work was also supported by national funds from FCT in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences-UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB. The authors acknowledge the COMBINE project “CombinatiOn aptaMer-drug Based therapeutics for ocular neovascular dIsease: wheN two are bettEr than one”, funded by BInov 2021, Innovation Grant of the Southern Regional Section and Autonomous Regions (SRSRA) of Portuguese Pharmacists Order.

Funding

Fundação para a Ciência e a Tecnologia (Grant no. SFRH/BD/112526/2015, UIDB/00709/2020, UIDP/04378/2020, UIDP/00709/2020, UIDB/04378/2020); European Regional Development Fund (Grant no. Centro-01-0145-FEDER-000019-C4); Fondo Europeo de Desarrollo Regional (Grant no. PT17/0019/0001); Spanish Government (Grant no. SEV2017-0712); Portuguese Pharmacists Order (Grant no. BInov 2021)

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Author notes

  1. Alberto Paradela, Cândida T. Tomaz and Luís António Paulino Passarinha are co-senior authors.

Authors and Affiliations

  1. Health Sciences Research Centre (CICS-UBI), Universidade da Beira Interior, 6201-001, Covilhã, Portugal

    Fátima Milhano dos Santos, Joana Mesquita, João Paulo Castro de Sousa, Cândida Teixeira Tomaz & Luís António Paulino Passarinha

  2. Functional Proteomics Laboratory, Centro Nacional de Biotecnología (CNB-CSIC), Unidad de Proteomica, Calle Darwin 3, Campus de Cantoblanco, 28049, Madrid, Spain

    Fátima Milhano dos Santos, Sergio Ciordia & Alberto Paradela

  3. C4-UBI, Cloud Computing Competence Centre, University of Beira Interior, 6200-501, Covilhã, Portugal

    Cândida Teixeira Tomaz

  4. Department of Ophthalmology, Centro Hospitalar de Leiria, 2410-197, Leiria, Portugal

    João Paulo Castro de Sousa

  5. Chemistry Department, Faculty of Sciences, Universidade da Beira Interior, 6201-001, Covilhã, Portugal

    Cândida Teixeira Tomaz

  6. Associate Laboratory i4HB, Faculdade de Ciências e Tecnologia, Institute for Health and Bioeconomy, Universidade NOVA, 2819-516, Caparica, Portugal

    Luís António Paulino Passarinha

  7. UCIBIO–Applied Molecular Biosciences Unit, Departamento de Química, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, 2829-516, Caparica, Portugal

    Luís António Paulino Passarinha

  8. Pharmaco-Toxicology Laboratory, UBIMedical, Universidade da Beira Interior, 6200-000, Covilhã, Portugal

    Luís António Paulino Passarinha

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  1. Fátima Milhano dos Santos
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  2. Sergio Ciordia
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Contributions

FMS: conceptualization, formal analysis, writing—original draft, and writing—review and editing. SC: conceptualization; writing—review and editing. JM: conceptualization; writing—review and editing. JPCS: conceptualization; writing—review and editing. AP: supervision; writing—review and editing. CTT: supervision, conceptualization, and writing—review and editing. LAPP: supervision, conceptualization, and writing—review and editing.

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Correspondence to Fátima Milhano dos Santos or Luís António Paulino Passarinha.

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dos Santos, F.M., Ciordia, S., Mesquita, J. et al. Vitreous humor proteome: unraveling the molecular mechanisms underlying proliferative and neovascular vitreoretinal diseases. Cell. Mol. Life Sci. 80, 22 (2023). https://doi.org/10.1007/s00018-022-04670-y

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  • DOI: https://doi.org/10.1007/s00018-022-04670-y

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