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Table 1 Pro-angiogenic and anti-angiogenic factors involved in the angiogenesis process

From: Recent advances in ocular drug delivery systems and targeting VEGF receptors for management of ocular angiogenesis: A comprehensive review

Factor

Type

Function

Properties

References

VEGF

Angiogenic

Stimulator of angiogenesis

Produced in the eye by retinal pigment epithelial cells

Upregulated by hypoxic condition

Contains 5 ligands {VEGF-A, B, C, D and placental growth factor (PGF)}

Consists of three protein-tyrosine kinases {(VEGFR-1, Flt-1), (VEGFR-2, Flk-1/KDR), (VEGFR-3)}

Two non-protein kinase co-receptors: neuropilin-1 and neuropilin-2

[17,18,19,20]

EGF & TGF

Angiogenic

Associated with signaling pathway in cancer & enhances cell proliferation process, leads to metastasis besides decreased apoptosis

Binds to VEGF receptors

Mitogens for endothelial cells in vitro, in vivo

[21, 22]

Angiopoietins

Angiogenic

Promotes angiogenesis in the uterus or embryonic vascular development

Paracrine growth factor

Contains 4 ligands Angiopoietin 1, 2, 3, 4 (Ang-1, 2, 3, 4)

Two corresponding tyrosine-kinase receptors (Tie-1 and Tie-2)

[23,24,25]

FGF

Angiogenic

Stimulates angiogenesis

FGF contains mainly FGF-1 and FGF-2 and it is also called acidic and basic FGF

FGF-1 (acidic FGF) and FGF-2 (basic FGF)

[26]

MMP

Angiogenic

Degradation of the basement membrane

Belongs to the category of soluble and membrane tied proteolytic enzymes

[27]

PEDF

Anti-angiogenic

Promotes endothelial cell apoptosis

Also known as serpin F1

Secreted by retinal epithelial cells

First factor is described for its neurotrophic properties in vitro

[28, 29]

Prolactin

Anti-angiogenic

Suppresses cell proliferation process also stimulates expression of plasminogen activator inhibitor

N-terminal 16-kDa fragment

16 K-PRL is a natural inhibitor of ocular angiogenesis

[30, 31]

Angiostatin

Anti-angiogenic

Inhibits ATP synthesis and that slows down migration of EC and proliferation

It is a fragment of protein plasminogen

Plasminogen and angiostatin can be synthesized by corneal layers

[19]

Vaso inhibins

Anti-angiogenic

It blocks inducers of angiogenesis (VEGF, FGF, etc.) through in vitro and in vivo

It can be generated by various proteases (MMP’s)

[32]

Endostatin

Anti-angiogenic

Suppresses migration and proliferation of endothelial cells and increases apoptosis

Derived from collagen XVIII

[19]

Thrombospondin

Anti-angiogenic

Assists in tumor death

First discovered in activated platelets

Contains five multifunctional proteins that can bind extracellular calcium that is TSP-1 to TSP-5

[33]

  1. VEGF vascular endothelial growth factor, PGF placental growth factor, KDR kinase-insert-domain receptor, EGF epidermal growth factor, TGF transforming growth factor, FGF fibroblast growth factor, MMP matrix metalloproteinase, PEDF pigment epithelium-derived factor, EC endothelial cells