Advances in neovascularization after diabetic ischemia

Table 1 Mechanisms and functions of proangiogenic factors

Trigger factors	Mechanism	Function	Ref.
HIF	When hypoxia occurs, HIF-α dimerizes with HIF-β, binding to hypoxia response elements in the nucleus, transcribing thousands of genes and promoting angiogenesis	Promote angiogenesis and increase vascular density; stimulate collateral vessel compensatory formation; regulate EPO and other downstream factors; mobilize endothelial progenitor cells	[21-24]
Macrophages	Macrophages are divided into M1 type, which is proinflammatory and phagocytic, and M2 type, which is anti-inflammatory and promotes angiogenesis	Transform into perivascular cells to control vascular permeability; remodel extracellular matrix to provide conduit for apical cells and promote blood vessel germination; endothelial cells and trim abnormal blood vessels	[25-30]
Monocytes	Angiogenesis is directly dependent on the number of circulating monocytes	Induce HIF-mediated release of chemokines and growth factors to stimulate angiogenesis; express angiogenin receptor Tie-2 and exacerbate inflammation	[7,31]
VEGF family	VEGF-A regulates angiogenesis, vascular permeability and inflammation. VEGF-B regulates angiogenesis and apoptosis. VEGF-C and VEGF-D regulate lymphangiogenesis, apoptosis and fiber formation	VEGF activates a variety of downstream signaling pathways and promotes the proliferation, migration and vascular remodeling of ECs; activate ERK1/2 and promote angiogenesis	[32-34]
Noncoding RNAs	Many noncoding RNAs regulate complex processes of angiogenesis	MiR-25-3p enhances endothelial permeability and angiogenesis. MiR-590-5p subtype NF90 has angiogenic effects	[35,36]
HGF	Stimulates angiogenesis by inducing endothelial cell proliferation, migration and tubular blood vessel formation	HGF significantly increases the expression of VEGF, decreases the activation of NF-κB and vascular leakage, promotes angiogenesis, is anti-inflammatory, is anti-oxidative and reduces vascular permeability	[37]
Angiotensin II	Angiogenesis is induced by activation of angiotensin 1 receptor and nicotinamide adenine dinucleotide phosphate oxidase	Induction of angiotensin II synthesis can lead to a proangiogenic state	[38]
asTF	asTF is widely expressed in macrophages and neovascularization in AS plaques	asTF affects all key stages of angiogenesis, including proliferation, migration and differentiation and induces increased levels of HIF and VEGF to promote angiogenesis	[39]
Classical Wnt pathway	Under the influence of Wnt factor, β-catenin isolates and enters the nucleus, binding to TCF/LEF and initiating transcription of downstream genes	The Wnt pathway promotes angiogenesis by regulating endothelial cell proliferation	[40,41]

AS: Atherosclerosis; asTF: Alternatively spliced tissue factor; EC: Endothelial cell; EPO: Erythropoietin; HGF: Hepatocyte growth factor; HIF: Hypoxia inducible factor; MiR: MicroRNA; NF-κB: Nuclear factor kappa-B; VEGF: Vascular endothelial growth factor.

Table 2 Mechanisms and functions of the antiangiogenic factors

Inhibitory factor	Mechanism	Function	Ref.
Platelet reactive protein-1 (TSP-1)	TSP-1 levels increase under hypoxia	TSP-1 inhibits angiogenesis by stimulating endothelial cell apoptosis and inhibiting endothelial cell migration and proliferation as well as inhibiting VEGF and eNOS	[42,43]
IL-12	IL-12 stimulates the expression of proinflammatory and antiangiogenic genes in monocytes	Neutralization of IL-12 can enhance angiogenesis in ischemic areas and reduce body dysfunction	[7,44]
Noncoding RNAs	Noncoding RNA has the dual role of promoting and inhibiting angiogenesis	Upregulation of MiR-15a and MiR-16 reduce Tie2 protein levels and inhibit angiogenesis	[35,36]

eNOS: Endothelial nitric oxide synthase; IL-12: Interleukin 12; MiR: MicroRNA; TSP-1: Thrombospondin-1; VEGF: Vascular endothelial growth factor.