Angiogenesis, the formation of new blood vessels, plays a central role in a variety of physiological and pathological processes such as embryonic development, wound healing and tumor growth. It is a complex, multi-step process that involves the migration and proliferation of capillary endothelial cells. Several factors that stimulate the proliferation of endothelial cells in vitro have been shown to induce angiogenesis in vivo. Among these angiogenic growth factors are wide-spectrum multifunctional mitogens (e.g. the fibroblast growth factors) and the recently identified factors with distinct specificity for vascular endothelial cells (e.g. the platelet-derived endothelial cell growth factor). Another group of factors apparently induce angiogenesis indirectly (e.g. transforming growth factor-beta) by stimulating target cells to release angiogenic factors or by other mechanisms. The differential expression, release and activation of these factors might regulate angiogenesis under various physiological and pathological conditions.
Fibroblast growth factor
The fibroblast growth factors (FGF) are a family of cell signalling proteins that are involved in a wide variety of processes, most notably as crucial elements for normal development. An important function of FGF1 and FGF2 is to promote endothelial cell proliferation and physically organize endothelial cells into a tubular structure. Thus, they promote angiogenesis, growing new blood vessels from pre-existing vasculature. FGF1 and FGF2 are more potent angiogenic factors than vascular endothelial growth factor (VEGF) or platelet-derived growth factor (PDGF). FGF1 has been shown to induce cardiac angiogenesis in clinical laboratory studies. As well as stimulating blood vessel growth, FGFs are also important in wound healing. FGF1 and FGF2 stimulate angiogenesis and fibroblast proliferation, thereby forming granulation tissue, thereby filling the wound space/cavity early in the wound healing process. FGF7 and FGF10 (Figure 1) stimulate the repair of damaged skin and mucosal tissues by stimulating proliferation, migration and differentiation of epithelial cells, which have direct chemotactic effects on tissue remodeling.
Figure 1. Structure of the fibroblast growth factors 10 protein.
Platelet-derived growth factor (PDGF)
Platelet-derived growth factor (PDGF) is a common peptide regulator that stimulates connective tissue proliferation. It is synthesized by bone marrow macrophages and stored in platelet Q particles. PDGF is a basic glycoprotein with a molecular weight of 28 to 35 kD and is a dimer of two polypeptide chains formed by two subunits (A chain and B chain) bonded by disulfide bonds. PDGF is an important mitogen that stimulates the division and proliferation of vascular smooth muscle cells, fibroblasts, glial cells and other cells. It has a regulatory effect on individual development and cell differentiation, and plays an important role in wound healing.
The PDGF family has two major members: PDGF and vascular endothelial growth factor (VEGF), which have similar structures but bind to different receptors and produce different effects. PDGF mainly acts on mesenchymal cells such as fibroblasts and glial cells, while VEGF acts on endothelial cells.
Figure 2. Platelet-derived growth factor BB monomer, Human.
PDGF receptor PDGFR is classified as a receptor tyrosine kinase (RTK), a cell surface receptor. Two types of PDGFR have been identified: alpha and beta PDGFR. α-type binds to PDGF-AA, PDGF-BB and PDGF-AB, while β-type PDGFR has high affinity with PDGF-BB and PDGF-AB. PDGF binds to a PDGFR ligand binding pocket located within the second and third immunoglobulin domains. Upon activation by PDGF, these receptors dimerize and "turn on" by autophosphorylation at several sites on their cytoplasmic domains, which mediate cofactor binding and subsequent activation of signals Transduction, for example, by the PI3K pathway or reactive oxygen species (ROS) mediated activation of the STAT3 pathway. Its downstream effects include gene expression and regulation of the cell cycle. The role of PI3K has been studied in several laboratories. A growing body of data suggests that although this molecule is usually part of the growth signal complex, it plays a more important role in controlling cell migration. Different ligand isoforms have variable affinities for receptor isoforms, and receptor isoforms can variably form heterodimers or homodimers. This leads to the specificity of downstream signaling. The sis oncogene has been shown to be derived from the PDGFB chain gene. PDGF-BB is the highest affinity ligand for PDGFR-beta; PDGFR-β is a key marker of hepatic stellate cell activation during fibrosis.
Transforming growth factor-beta
Transforming growth factor beta (TGF-beta) is a multifunctional cytokine belonging to the transforming growth factor superfamily, including three different mammalian isoforms and many others. Signal protein. The TGF-β protein is produced by all leukocyte lineages. Activated TGF-β complexes with other factors to form a serine/threonine kinase complex that binds to the TGF-β receptor. The TGF-beta receptor consists of type 1 and type 2 receptor subunits. Upon binding of TGF-β, type 2 receptor kinase phosphorylates and activates type 1 receptor kinase, thereby activating the signal cascade. This results in activation of different downstream substrates and regulatory proteins, inducing transcription of different target genes that play a role in the differentiation, chemotaxis, proliferation and activation of many immune cells.
Figure 3. Structure of the Transforming growth factor beta.
In normal cells, TGF-β acts through its signaling pathway, causing it to stop the cell cycle in the G1 phase, thereby stopping proliferation, inducing differentiation or promoting apoptosis. In many cancer cells, a portion of the TGF-β signaling pathway is mutated, and TGF-β no longer controls the cell. These cancer cells proliferate. The surrounding stromal cells (fibroblasts) also proliferate. Both cells increase their production of TGF-β. This TGF-β acts on surrounding stromal cells, immune cells, endothelial cells and smooth muscle cells. It causes immunosuppression and angiogenesis, making cancer more invasive.
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