Copyright ©The Author(s) 2022.
World J Diabetes. Nov 15, 2022; 13(11): 926-939
Published online Nov 15, 2022. doi: 10.4239/wjd.v13.i11.926
Table 1 Mechanisms and functions of proangiogenic factors
Trigger factors
HIFWhen hypoxia occurs, HIF-α dimerizes with HIF-β, binding to hypoxia response elements in the nucleus, transcribing thousands of genes and promoting angiogenesisPromote angiogenesis and increase vascular density; stimulate collateral vessel compensatory formation; regulate EPO and other downstream factors; mobilize endothelial progenitor cells[21-24]
MacrophagesMacrophages are divided into M1 type, which is proinflammatory and phagocytic, and M2 type, which is anti-inflammatory and promotes angiogenesisTransform 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]
MonocytesAngiogenesis is directly dependent on the number of circulating monocytesInduce HIF-mediated release of chemokines and growth factors to stimulate angiogenesis; express angiogenin receptor Tie-2 and exacerbate inflammation[7,31]
VEGF familyVEGF-A regulates angiogenesis, vascular permeability and inflammation. VEGF-B regulates angiogenesis and apoptosis. VEGF-C and VEGF-D regulate lymphangiogenesis, apoptosis and fiber formationVEGF 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 RNAsMany noncoding RNAs regulate complex processes of angiogenesisMiR-25-3p enhances endothelial permeability and angiogenesis. MiR-590-5p subtype NF90 has angiogenic effects[35,36]
HGFStimulates angiogenesis by inducing endothelial cell proliferation, migration and tubular blood vessel formationHGF 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 IIAngiogenesis is induced by activation of angiotensin 1 receptor and nicotinamide adenine dinucleotide phosphate oxidaseInduction of angiotensin II synthesis can lead to a proangiogenic state[38]
asTFasTF is widely expressed in macrophages and neovascularization in AS plaquesasTF 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 pathwayUnder the influence of Wnt factor, β-catenin isolates and enters the nucleus, binding to TCF/LEF and initiating transcription of downstream genesThe Wnt pathway promotes angiogenesis by regulating endothelial cell proliferation[40,41]
Table 2 Mechanisms and functions of the antiangiogenic factors
Inhibitory factor
Platelet reactive protein-1 (TSP-1)TSP-1 levels increase under hypoxiaTSP-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-12IL-12 stimulates the expression of proinflammatory and antiangiogenic genes in monocytesNeutralization of IL-12 can enhance angiogenesis in ischemic areas and reduce body dysfunction[7,44]
Noncoding RNAsNoncoding RNA has the dual role of promoting and inhibiting angiogenesisUpregulation of MiR-15a and MiR-16 reduce Tie2 protein levels and inhibit angiogenesis[35,36]