Table 2.

Endogenous Inhibitors of Angiogenesis

Inhibitor	Mechanism of action	Refs
Thrombospondin-1	Platelet-derived 450 kD protein, binds CD 36 on ECs	[37]
Cleavage products of ECM
Endostatin	20 kD C-terminal fragment of collagen XVIII, multiple pathways, incl. alpha5beta1 integrin	[171, 172]
Tumstatin	Cleavage fragment of alpha3 chain of type IV collagen, activity mediated by alphavbeta3 integrin	[41]
Arresten	26-kDa NC1 domain of the alpha1 chain of type IV collagen, activity mediated by alpha1beta1 integrin	[53]
Canstatin	24 kD fragment of alpha2 chain of type IV collagen, activity via proapoptotic pathways in ECs	[54, 173]
Vastatin	NC1 domain of type VIII collagen (alpha 1), induces cell cycle arrest and apoptosis	[55]
Restin	22 kD collagen XV fragment, inhibits EC migration, induces apoptosis	[56, 174]
Plasma proteins
Angiostatin	38 kD internal fragment of plasminogen, binds ATP synthase, angiomotin, and alphavbeta3 integrin, multiple mechanisms of action	[60]
16-kd prolactin fragment	16 kD N-terminal fragment of prolactin, inhibits EC proliferation, induces apoptosis	[64, 65, 175]
Chemokines
Platelet factor-4	Chemokine with antiproliferative and antimigratory properties on ECs	[176]
Interferon-inducible protein-10 (IP-10)	Member of CXC chemokine family, potent immunomodulatory and antiangiogenic activity	[74]
Angiopoietins	Bind EC-specific receptor Tie2, complex roles in angiogenesis	[76]
Interleukins
IL-12	Heterodimeric pro-inflammatory cytokine, antiangiogenic effects via induction of IFN-gamma and IP-10	[78, 79]
IL-18	Cytokine with antiangiogenic activity via induction of IFN-gamma	[86]
Interferons	Multifunctional cytokines that regulate antiviral, antitumor, and cellular immune responses, potent antiangiogenic properties via inhibition of bFGF	[92]
Endothelial-monocyte activating polypeptide II (EMAP II)	Tumor-derived cytokine, induces tissue factor, upregulates TNF receptor 1, E-selectin and P-selectin on ECs, induces EC apoptosis	[94]
Tissue inhibitors of metalloproteinases (TIMPs)	Block the activity of MMPs, complex role in tumor angiogenesis and tumor growth	[97]
Tumor necrosis factor alpha (TNF-alpha)	52 kD homotrimeric complex, potent vasculotoxic effects on tumors, activity mediated by TNF receptor	[99, 177]
p53	Tumor suppressor gene, wild-type antiangiogenic activity via increased thrombospondin-1 expression, decreased VEGF	[101, 102]
Serine protease inhibitors
Cleaved antithrombin III, maspin, pigment epithelium-derived factor (PEDF)	Potent antiangiogenic activities	[178-180]
Vascular endothelial growth inhibitor (VEGI)	Cytokine in the TNF superfamily expressed by ECs, promotes EC cell cycle arrest and apoptosis	[181, 182]
2-methoxyestradiol	Endogenous metabolite of estrogen, exerts antiangiogenic effects by inhibiting HIF-1alpha	[183]
Tetrahydrocortisol	Most potent naturally occurring angiostatic steroid	[184]
Secreted protein acidic and rich in cysteine (SPARC)/BM-40/osteonectin	34 kD matricellular protein, inhibits EC spread, abrogates binding of PDGF and VEGF to their receptors	[185, 186]
Domain 5 of high molecular weight kininogen (HMWK)/kininostatin	Cleaved component of HMWK inhibits EC proliferation and induces apoptosis by binding EC tropomyosin	[187-189]