TABLE I.
The most potent angiogenic growth factors and their mechanism of action.
| Growth factora | Ligand/receptor interactionb | Angiogenic functions |
|---|---|---|
| FGF | FGF-1(aFGF)/FGFR1,FGF-2(bFGF)/FGFR2 | Induces EC differentiation, proliferation, migration, adhesion and survival.63–66 |
| Induces the activation, proliferation and migration of other cell types such as EPC and SMCs.67,68 | ||
| Stimulates angioblast induction. | ||
| Induces vasculogenesis and the formation of immature primary vasculature.69 | ||
| Stimulates ECM degradation by upregulating the expression of proteases, MMPs and uPA.63 | ||
| Promotes collateral growth via upregulating PDGFR expression.70 | ||
| Binds to other cell surface or ECM molecules such as heparin, heparan sulfate proteoglycans (HSPGs) and integrins to enhance their own activity and stability, angiogenic EC response and neovascularization. | ||
| VEGF | VEGF/VEGFR1(Flt-1), VEGF/VEGFR2(Flk-1) | Induces vasculogenesis and the formation of immature primary vasculature.64,69 |
| Induces nascent vessel sprouting.21 | ||
| Induces EC proliferation, migration and survival.21,71,72 | ||
| Induces EC differentiation and arterial specialization.71,73 | ||
| Increases vascular permeability and establishes provisional matrix.74 | ||
| Stimulates protease activity to detach mural cells and degrade the basement membrane for matrix organization and new cell migration.71 | ||
| Stabilizes vessels by upregulating PDGF-β for mural cell recruitment.71 | ||
| Stimulates the remodeling of primary vasculature and recruitment of mural cells.21 | ||
| Inhibits apoptosis and senescence to enhance survival and vessel stability by suppressing p16, p21, p27 and upregulating PI3K/Akt and Bcl2.22,75 | ||
| Binds to other ECM molecules such as heparin and heparan sulfate proteoglycans (HSPGs) to enhance their own activity and stability, angiogenic EC response and neovascularization; and facilitates co-receptor neuropilin (NRP1) and VEGFR-2 binding.76 | ||
| VEGF-A165/VEGFR2(Flk-1), VEGF-A165/NP-1 | Enhances EC migration and arterial growth.77 | |
| VEGF-C/VEGFR3 | Regulates lymphatic vessel development.78 | |
| PIGF/VEGFR1 | Promotes trophoblast growth, angiogenesis and neovascularization.79 | |
| Regulates angiogenic switch by inducing EC proliferation, migration and survival, mobilizing BM-derived cells such as HSCs and recruiting SMCs for vessel stabilization.80 | ||
| PDGF | PDGF-BB/PDGFR-β | Stimulates vessel stabilization and maturation by recruiting MSCs, mural cell progenitors, pericytes and SMCs.81,82 |
| Promotes mural cell proliferation, migration and differentiation.71 | ||
| Regulates the production of ECM molecules from pericytes to establish basement membrane and ECM of blood vessels; and promote stabilization.20 | ||
| Contributes to remodeling by causing fibroblasts to secrete collagenases.20 | ||
| Promotes VEGF expression in vascular SMCs.83 | ||
| PDGF-AA/PDGFR-α | Regulates angiogenesis by increasing VEGF-A production.84 | |
| Angiopoietin | Ang-1/Tie-2 | Induces vessel stabilization and maturation by inhibiting VEGF activity and plasma leakage, recruiting mural cells, increasing type IV collagen deposition and stimulating EC-cell junction and EC-SMC interactions.19,69,85–87 |
| Regulates EC–EC communication.87 | ||
| Promotes EC survival by upregulating the expression of survivin, an anti-apoptotic gene through Akt signaling pathway.88 | ||
| Induces the escape from apoptosis by recruiting ABIN-2 that inhibits NFκB activity.89 | ||
| Recruits MSCs for their differentiation by TGF-β.81 | ||
| Ang-1/Tie-2, Ang-1/Tie-2 | Regulates tip cell and stalk cell fate determination of ECs (vascular polarity) by upregulating Dll4/Notch signaling.90 | |
| Ang-2/Tie-2 | Destabilizes vessels by detaching SMCs and relaxing underlying ECM.91 | |
| Prevents mural cell recruitment and blocks the activity of Ang-1.85 | ||
| Induces EC apoptosis and vessel regression in the absence of VEGF.21 | ||
| Induces EC proliferation and migration; and angiogenic sprouting in the presence of VEGF.21 | ||
| Ephrin | Ephrin-B2/EphB4 | Establishes arterial-venous vascular boundary identity.93 |
| Induces vessel sprouting and branching by ECs.92 | ||
| Stimulates vessel remodeling, stabilization and maturation by recruiting mural cells.21 | ||
| Ephrin-A1/EphA2 | Induces EC migration, proliferation, adhesion and vessel sprouting.93 | |
| TGF-β | TGF-β1/ALK1 | Promotes angiogenesis by inducing EC migration, proliferation and differentiation.94,95 |
| Promotes cell survival and tubule formation in vitro by activating PI3K/Akt and Mitogen-activated protein kinase (MAPK) pathways as well as autocrine secretion of TGF-α.96 | ||
| Upregulates VEGF expression by vascular ECs97; and Placental growth factor (PGF)98 and bFGF expression by SMCs to enhance angiogenesis.99 | ||
| TGF-β1/ALK5 | Inhibits angiogenesis by hindering EC activity.94 | |
| Guides vessel maturation.71 | ||
| TGF-β1/ TGF-βRII | Induces vessel stabilization and maturation by causing the differentiation of MSCs to mural cells and stimulating ECM deposition.19,71,81,100 | |
| Stimulates protease production for vascular remodeling.71 | ||
| HGF | HGF/HGFR | Induces EC proliferation, migration, survival and tubulogenesis.101 |
| Stimulates urokinase secretion by ECs.102 | ||
| Promotes VEGF expression on VSMCs.103 | ||
| Enhances VEGF-mediated angiogenesis by ECs.104 | ||
| SDF-1 | SDF-1/CXCR4(CD184) | Promotes angiogenesis by recruiting EPCs from BM; and regulating HSC migration and hematopoiesis reconstitution.105 |
| Promotes EC activity, differentiation and tubulogenesis; and inhibits EPC apoptosis.107,108 | ||
| Promotes vessel stabilization and maturation by recruiting SMC progenitors.108 | ||
| Promotes vascular remodeling by upregulating metalloproteinases110 and downregulating angiostatin.110,111 | ||
| Regulates the expression of proangiogenic VEGF-A, IL-6, IL-8 and tissue inhibitor of metalloproteinase-2 during vascularization.110 | ||
| SPARC | SPARCc | Promotes tubulogenesis of ECs.112 |
| Promotes pericyte recruitment by repressing endoglin-mediated TGF-β1 activity.113 | ||
| Promotes VEGFR2 activation by blocking anti-angiogenic action of VEGF-A/VEGFR-1 interaction.114 | ||
| Hinder EC and vSMC activity by inhibiting the activity of VEGFR1, FGF-2 and PDGF.115–120 |
a
FGF, fibroblast growth factor; aFGF, acidic fibroblast growth factor; bFGF, basic fibroblast growth factor; VEGF, vascular endothelial growth factor; PIGF, placental growth factor; PDGF, platelet-derived growth factor; Ang, angiopoietin; TGF-β, transforming growth factor β; HGF, hepatocyte growth factor; SDF-1, stromal cell-derived factor 1; SPARC, secreted protein acidic and rich in cysteine; EC, endothelial cell; EPC, endothelial progenitor cell; SMC, smooth muscle cell; MMP, matrix metalloproteinases; uPA, urokinase-type plasminogen activator.
b
FGFR, fibroblast growth factor receptor; VEGFR, vascular endothelial growth factor receptor; NP-1, neuropilin 1; PDGFR, platelet-derived growth factor; Tie-2, tyrosine kinase with Ig and EGF (epidermal growth factor) homology domains; Eph, ephrin receptor; ALK, anaplastic lymphoma kinase; TGF-βR, transforming growth factor β receptor; HGFR, hepatocyte growth factor receptor; CXCR4, C-X-C chemokine receptor type 4.
c
Uncharacterized receptor.