Table 1 A summary of angiogenic agents used in bone tissue engineering and their mechanism of action

Chemical agent

OCP

Direct effect on cell migration and proliferation. Indirect effect by recruiting macrophages that induce secretion of cytokines such as VEGF

[182]

Sr²⁺

Increases the level of pro-angiogenic factors (e.g., VEGF, MMP-2 and bFGF)

[72]

Co²⁺

Activation of the HIF-1α pathway

[183]

DMOG

Stimulation of the AKT/mTOR pathway in HUVECs

[123, 184]

Mg²⁺

Promotes VEGF and endothelial nitric oxide secretion

[185]

Fe³⁺

Increases the level of HIF-1α by decrease activation of prolyl hydroxylases

[186]

Drugs

Simvastatin

Enhances VEGF and HIF-1α expression

[44]

PTHrP-2 (PTH derivative)

Increases expression of angiogenesis-related genes such as FGF and VEGF

[187]

Deferoxamine

Activates the HIF-1α signal pathway and the overexpression of VEGF

[188, 189]

Erythropoietin

Forms the erythropoietin and the erythropoietin receptor complex

[190]

Small molecules

CASIN and AMD3100

Enhances proliferation and migration of ECs

[191]

ADTM

Enhances VEGF expression in vascular smooth muscle

[192]

α-Tocopherol

Affects VEGF-R2 signaling pathway

[47]

SalB

increase in VEGF and a major role on the Akt/mTOR/p70S6K signaling pathway

[167]

Eu³⁺

Stimulates immune response of macrophages

[193]

Salidroside

Increases VEGF and nitric oxide secretion

[194, 195]

SP

Increases migration of BMSCs and VEGF expression

[196]

GFs

PDGF

Increases VEGF expression

[197]

VEGF

Enhances ECs migration and increases vascular permeability

[198]

FGF

Enhances ECs proliferation and differentiation

[199, 200]

Genes

ZEB1

Activates the PI3K and p38 pathways

[201]

Foxc2

Activates PI3K and ERK

[202, 203]