Angiogenesis following vasculogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels,formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise (especially in older texts). The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.
The blood vessels are the part of the circulatory system, and microcirculation, that transports blood throughout the human body. These vessels are designed to transport nutrients and oxygen to the tissues of the body. They also take waste and carbon dioxide and carry them away from the tissues and back to the heart. Blood vessels are needed to sustain life as all of the body’s tissues rely on their functionality.There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and the tissues; and the veins, which carry blood from the capillaries back toward the heart. The word vascular, meaning relating to the blood vessels, is derived from the Latin vas, meaning vessel. Some structures -- such as cartilage, the epithelium, and the lens and cornea of the eye -- do not contain blood vessels and are labeled avascular.
Vasculogenesis is the process of blood vessel formation in the embryo, occurring by a de novo production of endothelial cells. It is sometimes paired with angiogenesis, as the first stage of the formation of the vascular network, closely followed by angiogenesis.
Endothelium refers to cells that line the interior surface of blood vessels and lymphatic vessels, forming an interface between circulating blood or lymph in the lumen and the rest of the vessel wall. It is a thin layer of simple, or single-layered, squamous cells called endothelial cells. Endothelial cells in direct contact with blood are called vascular endothelial cells, whereas those in direct contact with lymph are known as lymphatic endothelial cells.
Angiogenesis is a normal and vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. The essential role of angiogenesis in tumor growth was first proposed in 1971 by Judah Folkman, who described tumors as "hot and bloody,"illustrating that, at least for many tumor types, flush perfusion and even hyperemia are characteristic.
Wound healing is a complex process in which the skin, and the tissues under it, repair themselves after injury. In this article, wound healing is depicted in a discrete timeline of physical attributes (phases) constituting the post-trauma repairing process. In undamaged skin, the epidermis and dermis form a protective barrier against the external environment. When the barrier is broken, a regulated sequence of biochemical events is set into motion to repair the damage. This process is divided into predictable phases: blood clotting (hemostasis), inflammation, tissue growth (proliferation), and tissue remodeling (maturation). Blood clotting may be considered to be part of the inflammation stage instead of a separate stage.
Granulation tissue is new connective tissue and microscopic blood vessels that form on the surfaces of a wound during the healing process. Granulation tissue typically grows from the base of a wound and is able to fill wounds of almost any size. Examples of granulation tissue can be seen in pyogenic granulomas and pulp polyps. Its histological appearance is characterized by proliferation of fibroblasts and new thin-walled, delicate capillaries (angiogenesis), infiltrated inflammatory cells in a loose extracellular matrix.
An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels (angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical drugs or diet.
Sprouting angiogenesis was the first identified form of angiogenesis. It occurs in several well-characterized stages. First, biological signals known as angiogenic growth factors activate receptors on endothelial cells present in pre-existing blood vessels. Second, the activated endothelial cells begin to release enzymes called proteases that degrade the basement membrane to allow endothelial cells to escape from the original (parent) vessel walls. The endothelial cells then proliferate into the surrounding matrix and form solid sprouts connecting neighboring vessels.
In biochemistry and pharmacology, a receptor is a protein molecule that receives chemical signals from outside a cell. When such chemical signals bind to a receptor, they cause some form of cellular/tissue response, e.g. a change in the electrical activity of a cell. There are three main ways the action of the receptor can be classified: relay of signal, amplification, or integration. Relaying sends the signal onward, amplification increases the effect of a single ligand, and integration allows the signal to be incorporated into another biochemical pathway. In this sense, a receptor is a protein-molecule that recognizes and responds to endogenous chemical signals, e.g. an acetylcholine receptor recognizes and responds to its endogenous ligand, acetylcholine. However, sometimes in pharmacology, the term is also used to include other proteins that are drug targets, such as enzymes, transporters, and ion channels.
Enzymes are macromolecular biological catalysts. Enzymes accelerate chemical reactions. The molecules upon which enzymes may act are called substrates and the enzyme converts the substrates into different molecules known as products. Almost all metabolic processes in the cell need enzyme catalysis in order to occur at rates fast enough to sustain life. Metabolic pathways depend upon enzymes to catalyze individual steps. The study of enzymes is called enzymology and a new field of pseudoenzyme analysis has recently grown up, recognising that during evolution, some enzymes have lost the ability to carry out biological catalysis, which is often reflected in their amino acid sequences and unusual 'pseudocatalytic' properties.
A protease is an enzyme that helps proteolysis: protein catabolism by hydrolysis of peptide bonds. Proteases have evolved multiple times, and different classes of protease can perform the same reaction by completely different catalytic mechanisms. Proteases can be found in all forms of life and viruses.
As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in tandem, using adhesion molecules called integrins. These sprouts then form loops to become a full-fledged vessel lumen as cells migrate to the site of angiogenesis. Sprouting occurs at a rate of several millimeters per day, and enables new vessels to grow across gaps in the vasculature. It is markedly different from splitting angiogenesis because it forms entirely new vessels as opposed to splitting existing vessels.
Tandem, or in tandem, is an arrangement in which a team of machines, animals or people are lined up one behind another, all facing in the same direction.
Integrins are transmembrane receptors that facilitate cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, organization of the intracellular cytoskeleton, and movement of new receptors to the cell membrane. The presence of integrins allows rapid and flexible responses to events at the cell surface.
In biology, a lumen is the inside space of a tubular structure, such as an artery or intestine. It comes from Latin lumen, meaning 'an opening'.
By intussusception, also known as splitting angiogenesis, a new blood vessel is created by splitting of an existing blood vessel in two.
Intussusception was first observed in neonatal rats. In this type of vessel formation, the capillary wall extends into the lumen to split a single vessel in two. There are four phases of intussusceptive angiogenesis. First, the two opposing capillary walls establish a zone of contact. Second, the endothelial cell junctions are reorganized and the vessel bilayer is perforated to allow growth factors and cells to penetrate into the lumen. Third, a core is formed between the 2 new vessels at the zone of contact that is filled with pericytes and myofibroblasts. These cells begin laying collagen fibers into the core to provide an extracellular matrix for growth of the vessel lumen. 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.
A cell junction is a type of structure that exists within the tissue of some multicellular organisms, such as animals. Cell junctions consist of multiprotein complexes that provide contact between neighboring cells or between a cell and the extracellular matrix. They also build up the paracellular barrier of epithelia and control the paracellular transport. Cell junctions are especially abundant in epithelial tissues.
A bilayer is a double layer of closely packed atoms or molecules.
Pericytes are multi-functional cells that wrap around the endothelial cells that line the capillaries and venules throughout the body. Pericytes are embedded in basement membrane where they communicate with endothelial cells of the body's smallest blood vessels by means of both direct physical contact and paracrine signaling. In the brain, pericytes help sustain the blood–brain barrier as well as several other homeostatic and hemostatic functions of the brain. These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. Pericytes regulate capillary blood flow, the clearance and phagocytosis of cellular debris, and the permeability of the blood–brain barrier. Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. A deficiency of pericytes in the central nervous system can cause the blood–brain barrier to break down.
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.This may be due to an increase in the production of nitric oxide during exercise. Nitric oxide results in vasodilation of blood vessels.
Nitric oxide is a colorless gas with the formula NO. It is one of the principal oxides of nitrogen. Nitric oxide is a free radical, i.e., it has an unpaired electron, which is sometimes denoted by a dot in its chemical formula, i.e., ·NO. Nitric oxide is also a heteronuclear diatomic molecule, a historic class that drew researches which spawned early modern theories of chemical bonding.
Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g integrins and prostaglandins, including several growth factors e.g. VEGF, FGF.
|FGF||Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts|
|VEGFR and NRP-1||Integrate survival signals|
|Ang1 and Ang2||Stabilize vessels|
|PDGF (BB-homodimer) and PDGFR||recruit smooth muscle cells|
|TGF-β, endoglin and TGF-β receptors||↑extracellular matrix production|
|CCL2||Recruits lymphocytes to sites of inflammation|
|Integrins αVβ3, αVβ5 (? ) and α5β1||Bind matrix macromolecules and proteinases|
|VE-cadherin and CD31||endothelial junctional molecules|
|ephrin||Determine formation of arteries or veins|
|plasminogen activators||remodels extracellular matrix, releases and activates growth factors|
|plasminogen activator inhibitor-1||stabilizes nearby vessels|
|eNOS and COX-2|
|AC133||regulates angioblast differentiation|
|ID1/ID3||Regulates endothelial transdifferentiation|
|Class 3 semaphorins||Modulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeability|
The fibroblast growth factor (FGF) family with its prototype members FGF-1 (acidic FGF) and FGF-2 (basic FGF) consists to date of at least 22 known members.Most are single-chain peptides of 16-18 kDa and display high affinity to heparin and heparan sulfate. 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. FGF-1 stimulates the proliferation and differentiation of all cell types necessary for building an arterial vessel, including endothelial cells and smooth muscle cells; this fact distinguishes FGF-1 from other pro-angiogenic growth factors, such as vascular endothelial growth factor (VEGF), which primarily drives the formation of new capillaries.
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. FGF-2 is a more potent angiogenic factor than VEGF or PDGF (platelet-derived growth factor); however, it is less potent than FGF-1. As well as stimulating blood vessel growth, aFGF (FGF-1) and bFGF (FGF-2) are important players in wound healing. They stimulate the proliferation of fibroblasts and endothelial cells that give rise to angiogenesis and developing granulation tissue; both increase blood supply and fill up a wound space/cavity early in the wound-healing process.
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.Upregulation of VEGF is a major component of the physiological response to exercise and its role in angiogenesis is suspected to be a possible treatment in vascular injuries. In vitro studies clearly demonstrate that VEGF is a potent stimulator of angiogenesis because, in the presence of this growth factor, plated endothelial cells will proliferate and migrate, eventually forming tube structures resembling capillaries. VEGF causes a massive signaling cascade in endothelial cells. Binding to VEGF receptor-2 (VEGFR-2) starts a tyrosine kinase signaling cascade that stimulates the production of factors that variously stimulate vessel permeability (eNOS, producing NO), proliferation/survival (bFGF), migration (ICAMs/VCAMs/MMPs) and finally differentiation into mature blood vessels. Mechanically, VEGF is upregulated with muscle contractions as a result of increased blood flow to affected areas. The increased flow also causes a large increase in the mRNA production of VEGF receptors 1 and 2. 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.Ang1 and Ang2 are protein growth factors which act by binding their receptors, Tie-1 and Tie-2; while this is somewhat controversial, it seems that cell signals are transmitted mostly by Tie-2; though some papers show physiologic signaling via Tie-1 as well. 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.These enzymes are highly regulated during the vessel formation process because destruction of the extracellular matrix would decrease the integrity of the microvasculature.
Delta-like ligand 4 (DII4) is a protein with a negative regulatory effect on angiogenesis.Dll4 is a transmembrane ligand, for the notch family of receptors.
Class 3 Semaphorins (SEMA3s) regulate angiogenesis by modulating endothelial cell adhesion, migration, proliferation, survival and the recruitment of pericytes.Furthermore, semaphorins can interfere with VEGF-mediated angiogenesis since both SEMA3s and VEGF-A compete for Neuropilin receptor binding at endothelial cells. The relative expression levels of SEMA3s and VEGF-A may therefore be important for angiogenesis.
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.g Heart Disease sufferers.Application of specific compounds that may inhibit or induce the creation of new blood vessels in the body may help combat such diseases. 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.[ citation needed ]
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.On the other hand, an obstacle of protein therapy is the mode of delivery. 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. However, tumors need a dedicated blood supply to provide the oxygen and other essential nutrients they require in order to grow beyond a certain size (generally 1–2 mm3).
Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g. 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.Other clinicians believe angiogenesis really serves as a waste pathway, taking away the biological end products secreted by rapidly dividing cancer cells. 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. 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. 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. The subsequent growth of such metastases will also require a supply of nutrients and oxygen and a waste disposal pathway.
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. These then travel to already established, nearby blood vessels and activates their endothelial cell receptors. This induces a release of proteolytic enzymes from the vasculature. These enzymes target a particular point on the blood vessel and cause a pore to form. This is the point where the new blood vessel will grow from. The reason tumour cells need a blood supply is because they cannot grow any more than 2-3 millimeters in diameter without an established blood supply which is equivalent to about 50-100 cells.
Angiogenesis represents an excellent therapeutic target for the treatment of cardiovascular disease. It is a potent, physiological process that underlies the natural manner in which our bodies respond to a diminution of blood supply to vital organs, namely the production of new collateral vessels to overcome the ischemic insult.A large number of preclinical studies have been performed with protein-, gene- and cell-based therapies in animal models of cardiac ischemia, as well as models of peripheral artery disease. Reproducible and credible successes in these early animal studies led to high enthusiasm that this new therapeutic approach could be rapidly translated to a clinical benefit for millions of patients in the Western world suffering from these disorders. A decade of clinical testing both gene- and protein-based therapies designed to stimulate angiogenesis in underperfused tissues and organs, however, has led from one disappointment to another. Although all of these preclinical readouts, which offered great promise for the transition of angiogenesis therapy from animals to humans, were in one fashion or another, incorporated into early stage clinical trials, the FDA has, to date (2007), insisted that the primary endpoint for approval of an angiogenic agent must be an improvement in exercise performance of treated patients.
These failures suggested that either these are the wrong molecular targets to induce neovascularization, that they can only be effectively used if formulated and administered correctly, or that their presentation in the context of the overall cellular microenvironment may play a vital role in their utility. It may be necessary to present these proteins in a way that mimics natural signaling events, including the concentration, spatial and temporal profiles, and their simultaneous or sequential presentation with other appropriate factors.
Angiogenesis is generally associated with aerobic exercise and endurance exercise. While arteriogenesis produces network changes that allow for a large increase in the amount of total flow in a network, angiogenesis causes changes that allow for greater nutrient delivery over a long period of time. Capillaries are designed to provide maximum nutrient delivery efficiency, so an increase in the number of capillaries allows the network to deliver more nutrients in the same amount of time. A greater number of capillaries also allows for greater oxygen exchange in the network. This is vitally important to endurance training, because it allows a person to continue training for an extended period of time. However, no experimental evidence suggests that increased capillarity is required in endurance exercise to increase the maximum oxygen delivery.
Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet macular degeneration, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina, causing loss of vision. Anti-angiogenic drugs targeting the VEGF pathways are now used successfully to treat this type of macular degeneration
Angiogenesis of vessles from the host body into an implanted tissue engineered constructs is essential. Successful intergration is often dependent on thorough vascularisation of the construct as it provides oxygen and nutrients and prevents necrosis in the central areas of the implant. PDGF has been shown to stabilize vascularisation in collagen-glycosaminoglycan scaffolds.
Quantifying vasculature parameters such as microvascular density has various complications due to preferential staining or limited representation of tissues by histological sections. Recent research has shown complete 3D reconstruction of tumor vascular structure and quantification of vessel structures in whole tumors in animal models.
A growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation, healing, and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes.
Platelet-derived growth factor (PDGF) is one among numerous growth factors that regulate cell growth and division. In particular, PDGF plays a significant role in blood vessel formation, the growth of blood vessels from already-existing blood vessel tissue, mitogenesis, i.e. proliferation, of mesenchymal cells such as fibroblasts, osteoblasts, tenocytes, vascular smooth muscle cells and mesenchymal stem cells as well as chemotaxis, the directed migration, of mesenchymal cells. Platelet-derived growth factor is a dimeric glycoprotein that can be composed of two A subunits (PDGF-AA), two B subunits (PDGF-BB), or one of each (PDGF-AB).
Vascular endothelial growth factor (VEGF), originally known as vascular permeability factor (VPF), is a signal protein produced by cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.
Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.
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. Any irregularities in their function lead to a range of developmental defects. These growth factors generally act as systemic or locally circulating molecules of extracellular origin that activate cell surface receptors. A defining property of FGFs is that they bind to heparin and heparan sulfate, thus some of them are found to be sequestered in the extracellular matrix of tissues that contains heparan sulfate proteoglycans and they are released locally upon injury or tissue remodeling.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non receptor tyrosine kinases which do not possess transmembrane domains.
Angiopoietin is part of a family of vascular growth factors that play a role in embryonic and postnatal angiogenesis. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin cytokines are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.
Thrombospondin 1, abbreviated as THBS1, is a protein that in humans is encoded by the THBS1 gene.
CTGF, also known as CCN2 or connective tissue growth factor, is a matricellular protein of the CCN family of extracellular matrix-associated heparin-binding proteins. CTGF has important roles in many biological processes, including cell adhesion, migration, proliferation, angiogenesis, skeletal development, and tissue wound repair, and is critically involved in fibrotic disease and several forms of cancers.
VEGF receptors are receptors for vascular endothelial growth factor (VEGF). There are three main subtypes of VEGFR, numbered 1, 2 and 3. Also, they may be membrane-bound (mbVEGFR) or soluble (sVEGFR), depending on alternative splicing.
Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.
Angiogenesis is the process of forming new blood vessels from existing blood vessels. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteases (MMPs), a disintegrin and metalloprotease domain (ADAM), a disintegrin and metalloprotease domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.
Tumor-associated macrophages (TAMs) are a class of immune cells present in high numbers in the microenvironment of solid tumors. They are heavily involved in cancer-related inflammation. Macrophages are known to originate from bone marrow-derived blood monocytes or yolk sac progenitors, but the exact origin of TAMs in human tumors remains to be elucidated. The composition of monocyte-derived macrophages and tissue-resident macrophages in the tumor microenvironment depends on the tumor type, stage, size, and location, thus it has been proposed that TAM identity and heterogeneity is the outcome of interactions between tumor-derived, tissue-specific, and developmental signals.
Neuroangiogenesis is the coordinated growth of nerves and blood vessels. The nervous and blood vessel systems share guidance cues and cell-surface receptors allowing for this synchronised growth. The term neuroangiogenesis only came into use in 2002 and the process was previously known as neurovascular patterning. The combination of neurogenesis and angiogenesis is an essential part of embryonic development and early life. It is thought to have a role in pathologies such as endometriosis, brain tumors, and Alzheimer's disease.
Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. Across different cancer types, tumor-associated blood vessels have been discovered to differ significantly from normal blood vessels in morphology, gene expression, and functionality in ways that promote cancer progression. There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors.
A cancer-associated fibroblast (CAF) is a cell type within the tumor microenvironment that promotes tumorigenic features by initiating the remodelling of the extracellular matrix or by secreting cytokines. CAFs are a complex and abundant cell type within the tumour microenvironment; the number cannot decrease, as they are unable to undergo apoptosis.
Vasohibin-2 (VASH2) is a multifaceted protein that is encoded for by the VASH2 gene. As a vasohibin protein, VASH2 is closely associated with the vascular endothelial growth factor (VEGF) family of proteins as well. VASH2 has therefore been implicated in playing a vital role in blood vessel generation (angiogenesis), especially as it relates to tumor growth, but it has also been observed in association with neuron differentiation as well as ameliorating the symptoms of diabetic nephopathology.
VEGFR-2 inhibitor, also known as kinase insert domain receptor(KDR) inhibitor, are tyrosine kinase receptor inhibitors that reduce angiogenesis or lymphangiogenesis, leading to anticancer activity. Generally they are small, synthesised molecules that bind competitively to the ATP-site of the tyrosine kinase domain. VEGFR-2 selective inhibitor can interrupt multiple signaling pathways involved in tumor, including proliferation, metastasis and angiogenesis.