Mechanisms of Angiogenesis
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Finally, the core is fleshed out with no alterations to the basic structure. Intussusception is important because it is a reorganization of existing cells. It allows a vast increase in the number of capillaries without a corresponding increase in the number of endothelial cells. This is especially important in embryonic development as there are not enough resources to create a rich microvasculature with new cells every time a new vessel develops.
Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to shear stress acting on capillaries to cause angiogenesis, although current knowledge suggests that increased muscle contractions may increase angiogenesis. Nitric oxide results in vasodilation of blood vessels. Chemical stimulation of angiogenesis is performed by various angiogenic proteins e. In general, FGFs stimulate a variety of cellular functions by binding to cell surface FGF-receptors in the presence of heparin proteoglycans.
The FGF-receptor family is composed of seven members, and all the receptor proteins are single-chain receptor tyrosine kinases that become activated through autophosphorylation induced by a mechanism of FGF-mediated receptor dimerization. Receptor activation gives rise to a signal transduction cascade that leads to gene activation and diverse biological responses, including cell differentiation, proliferation, and matrix dissolution, thus initiating a process of mitogenic activity critical for the growth of endothelial cells, fibroblasts, and smooth muscle cells.
FGF-1 , unique among all 22 members of the FGF family, can bind to all seven FGF-receptor subtypes, making it the broadest-acting member of the FGF family, and a potent mitogen for the diverse cell types needed to mount an angiogenic response in damaged hypoxic tissues, where upregulation of FGF-receptors occurs. Besides FGF-1, one of the most important functions of fibroblast growth factor-2 FGF-2 or bFGF is the promotion of endothelial cell proliferation and the physical organization of endothelial cells into tube-like structures, thus promoting angiogenesis.
Mechanisms of angiogenesis | Nature
Vascular endothelial growth factor VEGF has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Initial in vitro studies demonstrated bovine capillary endothelial cells will proliferate and show signs of tube structures upon stimulation by VEGF and bFGF , although the results were more pronounced with VEGF.
Mechanically, VEGF is upregulated with muscle contractions as a result of increased blood flow to affected areas. The increase in receptor production means muscle contractions could cause upregulation of the signaling cascade relating to angiogenesis. As part of the angiogenic signaling cascade, NO is widely considered to be a major contributor to the angiogenic response because inhibition of NO significantly reduces the effects of angiogenic growth factors.
However, inhibition of NO during exercise does not inhibit angiogenesis, indicating there are other factors involved in the angiogenic response. The angiopoietins , Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse knock out studies. These receptors are tyrosine kinases. Thus, they can initiate cell signaling when ligand binding causes a dimerization that initiates phosphorylation on key tyrosines. Another major contributor to angiogenesis is matrix metalloproteinase MMP. MMPs help degrade the proteins that keep the vessel walls solid.
This proteolysis allows the endothelial cells to escape into the interstitial matrix as seen in sprouting angiogenesis.
Inhibition of MMPs prevents the formation of new capillaries. Delta-like ligand 4 DII4 is a protein with a negative regulatory effect on angiogenesis.
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Class 3 Semaphorins SEMA3s regulate angiogenesis by modulating endothelial cell adhesion, migration, proliferation, survival and the recruitment of pericytes. Angiogenesis inhibitor can be endogenous or come from outside as drug or a dietary component. Angiogenesis may be a target for combating diseases characterized by either poor vascularisation or abnormal vasculature E.
The presence of blood vessels where there should be none may affect the mechanical properties of a tissue, increasing the likelihood of failure. The absence of blood vessels in a repairing or otherwise metabolically active tissue may inhibit repair or other essential functions. Several diseases, such as ischemic chronic wounds , are the result of failure or insufficient blood vessel formation and may be treated by a local expansion of blood vessels, thus bringing new nutrients to the site, facilitating repair.
Other diseases, such as age-related macular degeneration , may be created by a local expansion of blood vessels, interfering with normal physiological processes. The modern clinical application of the principle of angiogenesis can be divided into two main areas: anti-angiogenic therapies, which angiogenic research began with, and pro-angiogenic therapies. Whereas anti-angiogenic therapies are being employed to fight cancer and malignancies,   which require an abundance of oxygen and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat cardiovascular diseases , the number one cause of death in the Western world.
One of the first applications of pro-angiogenic methods in humans was a German trial using fibroblast growth factor 1 FGF-1 for the treatment of coronary artery disease. Also, regarding the mechanism of action , pro-angiogenic methods can be differentiated into three main categories: gene-therapy , targeting genes of interest for amplification or inhibition; protein-therapy , which primarily manipulates angiogenic growth factors like FGF-1 or vascular endothelial growth factor , VEGF; and cell-based therapies, which involve the implantation of specific cell types.
There are still serious, unsolved problems related to gene therapy. Difficulties include effective integration of the therapeutic genes into the genome of target cells, reducing the risk of an undesired immune response, potential toxicity, immunogenicity , inflammatory responses, and oncogenesis related to the viral vectors used in implanting genes and the sheer complexity of the genetic basis of angiogenesis.
The most commonly occurring disorders in humans, such as heart disease, high blood pressure, diabetes and Alzheimer's disease , are most likely caused by the combined effects of variations in many genes, and, thus, injecting a single gene may not be significantly beneficial in such diseases. In contrast, pro-angiogenic protein therapy uses well-defined, precisely structured proteins, with previously defined optimal doses of the individual protein for disease states, and with well-known biological effects.
Oral, intravenous, intra-arterial, or intramuscular routes of protein administration are not always as effective, as the therapeutic protein may be metabolized or cleared before it can enter the target tissue. Cell-based pro-angiogenic therapies are still early stages of research, with many open questions regarding best cell types and dosages to use. Cancer cells are cells that have lost their ability to divide in a controlled fashion.
A malignant tumor consists of a population of rapidly dividing and growing cancer cells that progressively accrues mutations. Tumors induce blood vessel growth angiogenesis by secreting various growth factors e. VEGF and proteins. Growth factors such as bFGF and VEGF can induce capillary growth into the tumor, which some researchers suspect supply required nutrients, allowing for tumor expansion.
Unlike normal blood vessels, tumor blood vessels are dilated with an irregular shape. In either case, angiogenesis is a necessary and required step for transition from a small harmless cluster of cells, often said to be about the size of the metal ball at the end of a ball-point pen, to a large tumor.
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Angiogenesis is also required for the spread of a tumor, or metastasis. Single cancer cells can break away from an established solid tumor, enter the blood vessel, and be carried to a distant site, where they can implant and begin the growth of a secondary tumor. Evidence now suggests the blood vessel in a given solid tumor may, in fact, be mosaic vessels, composed of endothelial cells and tumor cells.
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This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of circulating tumor cells in the peripheral blood of patients with malignancies. Endothelial cells have long been considered genetically more stable than cancer cells. This genomic stability confers an advantage to targeting endothelial cells using antiangiogenic therapy, compared to chemotherapy directed at cancer cells, which rapidly mutate and acquire ' drug resistance ' to treatment. For this reason, endothelial cells are thought to be an ideal target for therapies directed against them.
The mechanism of blood vessel formation by angiogenesis is initiated by the spontaneous dividing of tumor cells due to a mutation. Angiogenic stimulators are then released by the tumor cells.
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These then travel to already established, nearby blood vessels and activates their endothelial cell receptors. Previous research by Rui Benedito's group showed that blood vessel cells resist and oppose these external mitogenic cues through an intercellular ligand-receptor signaling mechanism called Notch. The currently prevailing view is that increases in VEGF concentration or decreases in vascular Notch signaling stimulate both vascular cell proliferation and vessel growth.
Therefore, strategies aimed at stimulating mitogenesis and angiogenesis to treat cardiovascular disease are based on drugs that promote VEGF signaling or block natural angiogenesis inhibitors such as Notch. Using sophisticated genetic mouse models and cell imaging tools, Rui Benedito's group have now discovered that the effect of these drugs and signaling mechanisms varies with the stage of angiogenesis and the vascular context.
The results in the Nature Communications study indicate that high mitogenic stimulation induced by VEGF or Notch inhibition arrests the proliferation of angiogenic vessels, while at the same time inducing the proliferation of more mature vessels, which are less important for effective angiogenesis in the context of disease.
At high levels of mitogenic stimulus, the endothelial cells migrate and branch, but do not proliferate. Eventually, this affects the sustainable development of the blood vessels and the growth or regeneration of the surrounding tissues," says Rui Benedito. The newly identified mechanism could also explain the failure of several clinical trials seeking to boost angiogenesis in ischemic hearts after a myocardial infarction. Rui Benedito says that the results "significantly increase our understanding of the biology of blood vessels and will enable us to design better therapeutic strategies to induce effective angiogenesis in injured or ischemic tissues.
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