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Blood vessel formation, when new vessels emerge from existing vessels

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 mainly by processes of sprouting and splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. 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. 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.

Sprouting angiogenesis was the first identified form of angiogenesis and because of this, it is much more understood than intussusceptive angiogenesis. It occurs in several well characterized stages. The initial signal comes from tissue areas that are devoid of vasculature. The hypoxia that is noted in these areas causes the tissues to demand the presence of nutrients and oxygen that will allow the tissue to carry out metabolic activities. Because of this, parenchymal cells will secrete vascular endothelial growth factor (VEGF A) which is a proangiogenic growth factor. These biological signals activate receptors on endothelial cells present in pre existing blood vessels. Second, the activated endothelial cells, also known as tip 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. The cells that are proliferating are located behind the tip cells and are known as stalk cells.

Coalescent angiogenesis is a mode of angiogenesis, considered to be the opposite of intussusceptive angiogenesis, where capillaries fuse, or coalesce, to make a larger bloodvessel, thereby increasing blood flow and circulation. Coalescent angiogenesis has extended out of the domain of embryology. It is assumed to play a role in the formation of neovasculature, such as in a tumor.

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.

Chemical stimulation of angiogenesis is performed by various angiogenic proteins e. g. integrins and prostaglandins, including several growth factors e. g. VEGF, FGF.

Stimulator Mechanism FGF Promotes proliferation & differentiation of endothelial cells, smooth muscle cells, and fibroblasts VEGF Affects permeability 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 Histamine 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 transdifferentiationClass 3 semaphorinsModulates endothelial cell adhesion, migration, proliferation and apoptosis. Alters vascular permeabilityNogo A Regulates endothelial cell migration and proliferation. 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. 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. Dll4 is a transmembrane ligand, for the notch family of receptors. There have been many studies conducted that have served to determine consequences of the Delta like Ligand 4. One study in particular evaluated the effects of Dll4 on tumor vascularity and growth. In order for a tumor to grow and develop, it must have the proper vasculature. The VEGF pathway is vital to the development of vasculature that in turn, helps the tumors to grow. The combined blockade of VEGF and Dll4 results in the inhibition of tumor progression and angiogenesis throughout the tumor. This is due to the hindrance of signaling in endothelial cell signaling which cuts off the proliferation and sprouting of these endothelial cells. With this inhibition, the cells do not uncontrollably grow, therefore, the cancer is stopped at this point. if the blockade, however, were to be lifted, the cells would begin their proliferation once again.

Class 3 semaphorins (SEMA3s) regulate angiogenesis by modulating endothelial cell adhesion, migration, proliferation, survival and the recruitment of pericytes. The relative expression levels of SEMA3s and VEGF A may therefore be important for angiogenesis. 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. 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 replacement 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. By 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. 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. 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. Certain studies have indicated that vessels formed inside the tumor tissue are of higher irregularity and bigger in size, which is as well associated with poorer prognosis.

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 neoangiogenesis: the production of new collateral vessels to overcome the ischemic insult. 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. PDGF has been shown to stabilize vascularisation in collagen glycosaminoglycan scaffolds.

The first report of angiogenesis can be traced back to the book A treatise on the blood, inflammation, and gun shot wounds published in 1794, where Scottish anatomist John Hunter's research findings were compiled. In his study, Hunter observed the growth process of new blood vessels in rabbits. However, he did not coin the term "Angiogenesis," which is now widely used by scholars. Hunter also erroneously attributed the growth process of new blood vessels to the effect of an innate vital principle within the blood. The term "angiogenesis" is believed to have emerged not until the 1900s. The inception of modern angiogenesis research is marked by Judah Folkman's report on the pivotal role of angiogenesis in tumor growth.

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.