There are a number of factors that have been known to induce angiogenesis. There are mainly the following types：
Vascular endothelial growth factor (VEGF)
Vascular endothelial growth factor (VEGF), a homodimeric glycoprotein encoded by a single gene, directly stimulates endothelial cell migration, proliferation and division, and increases microvascular permeability. It is the mitogen that has the highest specificity for endothelial cells and the strongest angiogenic growth. VEGF binds to the high affinity of the two receptors KDR and Flt-1 on endothelial cells, directly stimulates the proliferation of vascular endothelial cells, induces migration and forms a lumen-like structure; it also increases microvascular permeability and causes plasma proteins. Extravasation (mainly fibrinogen) promotes neovascularization in vivo by inducing interstitial production. VEGF plays a central regulatory role in angiogenesis and formation and is a key angiogenic stimulator. Basic fibroblast growth factor (bFGF). TNF-α is a vasoactive cytokine that induces the release of ectopic endometrial inflammatory cytokines MCP-1, IL-6 and IL-8, and promotes ectopic endometrial and stromal cell proliferation and inflammation. Sexual cell infiltration, neovascularization, tissue adhesion, and the formation of ectopic lesions.
Figure 1. Structure of VEGF.
The interaction between vascular endothelial cells (EC) and extracellular matrix, between EC and EC, and between EC and other surrounding cells is required during angiogenesis. This effect is accomplished by adhesion factors, in which matrix metalloproteinases (MMPs) initiate activation and migration of endothelial cells by degrading basement membrane glycoproteins and extracellular matrix components, and the integrin family is mediated through binding to different ligands. The migration and adhesion of vascular endothelial cells contribute to the maturation and stabilization of new blood vessels. Cell adhesion molecules (ICAM-1) can produce immunosuppression and reduce the cytotoxicity of natural killer cells, helping ectopic tissues to escape the immune system. And the killing of natural killer cells, promoting angiogenesis after ectopic tissue invasion.
The mechanism of angiogenesis is complex, and there are many factors involved in and promoting angiogenesis. The number of macrophages in EMT peritoneal fluid is significantly increased, and the secretion of TNF-α and IL-8 can promote the proliferation of vascular endothelial cells, transforming growth factor-β ( TGF-β), platelet-derived endothelial cell growth factor (PD-ECGF), heparanase, angiopoietin (angs), and erythropoietin (Epo) are involved in the process of EMT angiogenesis.
Inhibitor Factors Type
Endostatin is a C-terminal fragment of XVIII collagen, which can specifically inhibit endothelial cell proliferation and promote apoptosis; inhibit angiogenic factors such as VEGF and bFGF, and biological effects, and also with matrix metalloproteinase and integrin ανβ3, Ανβ5 binds to inhibit migration and adhesion of endothelial cells and macrophages. It has a strong ability to inhibit the formation of new blood vessels and is the strongest endogenous angiogenesis inhibitor known to play an important role in the regulation of tumor angiogenesis.
Figure 2. Endostatin monomer, basic amino acid residues shown in red.
Other inhibitor Factors
Angiostatin is a 38Ku plasma plasminogen that selectively inhibits endothelial cell proliferation. Thrombospondin-1 (TSP-1) inhibits angiogenesis induced by VEGF or bFGF by interacting with the cell matrix. And there is concentration dependence. Tissue metalloproteinase inhibitors (TIMPs) inhibit angiogenesis by forming complexes with MMPs that inhibit MMPs activity, in addition, platelet factor-4 (PF-4), interferon-α (IFN-α), and interleukin13, interleukin4, interleukin10, plasminogen activator inhibitors, etc. can inhibit the process of angiogenesis.
Tumor angiogenesis is an extremely complex process, which generally includes steps including vascular endothelial matrix degradation, endothelial cell migration, endothelial cell proliferation, endothelial cell tube branching to form a vascular ring, and formation of a new basement membrane. The occurrence of tumor angiogenesis is due to the release of angiogenic factors from tumor cells to activate vascular endothelial cells, promote the proliferation and migration of endothelial cells, and on the other hand, the secretion of certain angiogenic factors by endothelial cells stimulates the growth of tumor cells. The interaction between tumor cells and endothelial cells runs through the entire process of tumor angiogenesis. Generally, tumor neocapsules are formed by extending and expanding on the basis of the original blood vessels, and the process is similar to typical wound healing and embryogenesis processes. These new blood vessels provide nutrients to the primary tumor that is continuously infiltrating and growing. In turn, the tumor cells secrete various substances during the growth process to accelerate the formation of new capillary blood vessels.
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