Ang is a family of secreted growth factors. This family is mainly composed of Ang-1, Ang-2, Ang-3 and Ang-4. The Ang-1 gene is located at 8p22 and has a molecular weight of about 70 kD. It is composed of 498 amino acids and contains 3 domains. 100 amino acids from the N-terminus are the first domain and have no homology; the 100th to 280 amino acids are The second domain is spirally coiled and has the typical characteristics of a secreted signal peptide; the 280-496 amino acids are the third domain, and its spatial division is very similar to that of the collagen family, which is called collagen-like fragment L3j. Angiopoietin is part of a series of angiogenic factors that play a role in embryonic and postnatal angiogenesis. There are four identified angiogenins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4. In addition, there are many proteins that are closely related to ("similar") angiopoietin (angiopoietin-related proteins 1, ANGPTL2, ANGPTL3, ANGPTL4, ANGPTL5, ANGPTL6, ANGPTL7, ANGPTL8). Angiopoietin-1 is essential for vascular maturation, adhesion, migration and survival. On the other hand, Angiopoietin-2 promotes cell death and destroys blood vessel formation. However, when used in combination with vascular endothelial growth factor (VEGF), it can promote new blood vessel formation.
Figure 1. Protein structure of angiogenins.
Tie2 is a tyrosine kinase receptor, and its ligands are A ng-1 and A ng-2. It has homology with immunoglobulin and epidermal growth factor (EGF) receptor, and mainly expresses in vascular endothelial cells. The Tie2 gene is located at 1p33～1p34, and the total length of mRNA is 4.4 kb. The protein precursor consists of 1124 amino acid residues. Ang-1 and Tie2 combine to form a dimer, which activates the latter by phosphorylation. The binding of Ang-2 to Tie2 can inhibit the latter's activity.
The Ang-1 gene is located at positions 8q22.3 to q23, and consists of 498 amino acids. The N-terminus has a hydrophobic secretion signal peptide and an alpha helix domain, and the C-terminus contains a fibrinogen-like domain. Ang-1 cannot directly promote the growth of endothelial cells in vitro, which may be different from the initiation of new blood vessels, but it plays a role in the formation of new blood vessel lumen and stabilizes the vascular structure. Ang-1 activates Tie2 after binding to the receptor. Tie2 activated endothelial cells can attract vascular smooth muscle cells, pericytes, etc., and support endothelial cells to form a complete blood vessel wall, thereby promoting angiogenesis. Interaction with the matrix and the like to maintain the stability of the vascular structure. Therefore, Ang-1 is mainly related to maintaining the interaction between endothelial cells and surrounding support cells, and plays an important role in maintaining the stability of vascular structure.
The Ang-2 gene is located at 8p23.1 and is mainly distributed in the ovary, uterus and placenta in normal adults, which may be related to the revascularization in these three tissues. Ang-2 is composed of 496 amino acids, has 60% homology with Ang-1, and can also bind to the receptor Tie2. Most scholars believe that Ang-2 is a Tie2 ligand with no signal transduction function. It does not cause the Tie2 receptor phosphorylation and can competitively block the effect of Ang-1.Other studies suggest that Ang-2 does not regulate endothelial cell proliferation during the regulation of angiogenesis, but binds to endothelial-specific Tie2, promotes or inhibits the phosphorylation of Tie2, and regulates vascular maturation through downstream pathways of the receptor. Therefore, the Ang-2/Tie2 signaling pathway plays a complex role in angiogenesis, and the specific mechanism needs further study.
The Ang-1 and Ang-2 / Tie2 signal transduction pathways play important roles in human physiological and pathological angiogenesis. This pathway is a new signal transduction pathway in addition to V EGF. Research on them helps to clarify the mechanism of angiogenesis and lays the foundation for the use of these targets for the treatment of related diseases. Ang-1 has the effect of promoting angiogenesis and stabilizing vascular structure. This characteristic of Ang-1 can be used with V EG F to treat vascular degenerative diseases; Ang-1 can increase the tightness of the connection between endothelial cells and can be used This feature reduces leakage of blood vessels and reduces inflammation. Ang-2 has dual effects on angiogenesis, and how to use A ng-2 to promote angiogenesis to treat vascular dysplasia is a topic worthy of research.