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Angiogenesis is a physiological process involving the growth of new blood vessels from pre-existing vessels. The blood vessels are part of the Circulatory system and function to transport Blood throughout the body Though there has been some debate over this, vasculogenesis is the term used for spontaneous blood-vessel formation, and intussusception is the term for new blood vessel formation by splitting off existing ones. Vasculogenesis is the process of Blood vessel formation occurring by a De novo production of endothelial cells. Intussusception is the process whereby a new Blood vessel is created by the splitting of an existing blood vessel in two

Angiogenesis is a normal process in growth and development, as well as in wound healing. Wound healing, or wound repair, is the body's natural process of regenerating dermal and epidermal tissue. However, this is also a fundamental step in the transition of tumors from a dormant state to a malignant state. See also Cancer A tumor or tumour is the name for a swelling or lesion formed by an abnormal growth of cells (termed neoplastic Malignant (from the Latin roots mal- = "bad" and -genus = "born" is a medical term used to describe a severe and progressively worsening disease

Contents

Types

Sprouting angiogenesis

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 present on endothelial cells present in pre-existing veins. The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the In the Circulatory system, a vein is a Blood vessel that carries Blood back toward the Heart (as opposed to Artery, a blood vessel Second, the activated endothelial cells begin to release enzymes called proteases that degrade the basement membrane in order to allow endothelial cells to escape from the original (parent) vessel walls. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link The basement membrane is a structure that supports overlying Epithelial or Endothelial cells. The endothelial cells then proliferate into the surrounding matrix and form solid sprouts connecting neighboring vessels. The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the In Biology, matrix (plural matrices) is the material between animal or plant cells, the material (or tissue in which more specialized structures are embedded As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in tandem, using adhesion molecules, the equivalent of cellular grappling hooks, called integrins. Tandem is a Latin Adverb meaning "at length" or "finally" Integrins are Cell surface receptors that interact with the Extracellular matrix (ECM and mediate various intracellular signals. These sprouts then form loops to become a full-fledged vessel lumen as cells migrate to the site of angiogenesis. A lumen (Lat lūmen, an opening or light (pl lumina is the inside space or lining of a tubular structure such as an artery or intestine Sprouting occurs at a rate of several millimeters per day, and enables new vessels to grow across gaps in the vasculature. The Millimetre ( American spelling: millimeter, symbol mm) is a unit of Length in the Metric system, equal to This is an article about the rock music band "Circulatory System" It is markedly different from splitting angiogenesis, however, because it forms entirely new vessels as opposed to splitting existing vessels [1].

Intussusceptive angiogenesis

Intussusception, also known as splitting angiogenesis, 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. A lumen (Lat lūmen, an opening or light (pl lumina is the inside space or lining of a tubular structure such as an artery or intestine 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. The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the A bilayer is a double layer of closely packed atoms or molecules See also Monolayer Lipid bilayer Perforation refers to the puncturing of a material with a harder (usually sharp object to create a hole or aperture The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. Third, a core is formed between the two new vessels at the zone of contact that is filled with pericytes and myofibroblasts. A pericyte, also known as Rouget cell or Mural cell, is a mesenchymal -like cell associated with the walls of small Blood vessels. A Myofibroblast is a cell that is in between a Fibroblast and a Smooth muscle cell in differentiation These cells begin laying collagen fibers into the core to provide an extracellular matrix for growth of the vessel lumen. Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells 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. Capillaries are the smallest of a body's Blood vessels measuring 5-10 μm in diameter which connect Arterioles and Venules and enable the interchange The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the 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.

Modern terminology of angiogenesis

Besides the differentiation between “Sprouting angiogenesis” and “Intussusceptive angiogenesis” there exists the today more common differentiation between the following types of angiogenesis:

Vasculogenesis – Formation of vascular structures from circulating or tissue-resident endothelial stem cells (angioblasts), which proliferate into de novo endothelial cells. Stem cells are cells found in most if not all multi-cellular Organisms. Blood vessels first make their appearance in several scattered vascular areas that are developed simultaneously between the Entoderm and the Mesoderm of the Yolk-sac This form particularly relates to the embryonal development of the vascular system.

Angiogenesis – Formation of thin-walled endothelium-lined structures with/without muscular smooth muscle wall and pericytes (fibrocytes). Smooth muscle is a type of non- Striated muscle, found within the Tunica media layer of large and small Arteries and Veins, the bladder A pericyte, also known as Rouget cell or Mural cell, is a mesenchymal -like cell associated with the walls of small Blood vessels. Fibrocyte is a very old term used to identify inactive mesenchymal cells that is cells showing minimal cytoplasmlimited amounts of rough endoplasmic reticulum and lack of biochemical This form plays an important role during the adult life span, also as "repair mechanism" of damaged tissues.

Arteriogenesis – Formation of medium-sized blood vessels possessing tunica media plus adventitia. The tunica media (or just media) ( middle coat) is the middle layer of an Artery or Vein. Adventitia is the outermost Connective tissue covering of any organ, vessel, or other structure

Because it turned out that even this differentiation is not a sharp one, today quite often the term “Angiogenesis” is used summarizing all different types and modifications of arterial vessel growth.

References

Therapeutic angiogenesis

Therapeutic angiogenesis is the application of specific compounds which may inhibit or induce the creation of new blood vessels in the body in order to combat disease. 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 retard repair or some other function. Several diseases (eg. 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. In Medicine, ischemia ( Greek ισχαιμία, isch- is restriction hema or haema is Blood) is a restriction 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 “angiogenesis” can be divided into two main areas: 1. Anti-angiogenic therapies (historically, research started with); 2. Pro-angiogenic therapies. Whereas anti-angiogenic therapies are trying to fight cancer and malignancies[2][3] (because tumors, in general, are nutrition- and oxygen-dependent, thus being in need of adequate blood supply), the pro-angiogenic therapies are becoming more and more important in the search of new treatment options for cardiovascular diseases (the number one cause of death in the Western world). One of the world-wide first applications of usage of pro-angiogenic methods in humans was a German trial using fibroblast growth factor 1 (FGF-1) for the treatment of coronary artery disease[4][5][6]. Today, clinical research is ongoing in various clinical trials to promote therapeutic angiogenesis for a variety of atherosclerotic diseases, like coronary heart disease, peripheral arterial disease, wound healing disorders, etc. [7].

Also, regarding the “mode of action”, pro-angiogenic methods can be differentiated into three main categories: 1. Gene-therapy; 2. Protein-therapy (using angiogenic growth factors like FGF-1 or vascular endothelial growth factor, VEGF); 3. Cell-based therapies.

There are still serious, unsolved problems related to gene therapy including: 1. Difficulty integrating the therapeutic DNA (gene) into the genome of target cells; 2. Risk of an undesired immune response; 3 Potential toxicity, immunogenicity, inflammatory responses and oncogenesis related to the viral vectors; and 4. The most commonly occurring disorders in humans such as heart disease, high blood pressure, diabetes, Alzheimer’s disease are most likely caused by the combined effects of variations in many genes, and thus injecting a single gene will not be beneficial in these 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. On the other hand, an obstacle of protein therapy is the mode of delivery: oral, intravenous, intra-arterial, or intramuscular routes of the protein’s administration are not always as effective as desired; the therapeutic protein can be metabolized or cleared before it can enter the target tissue. Cell-based pro-angiogenic therapies are still in an early stage of research – with many open questions regarding best cell types and dosages to use.

Mechanical stimulation

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[8]. This may be due to an increase in the production of nitric oxide during exercise.

Chemical stimulation

Chemical stimulation of angiogenesis is performed by various angiogenic proteins, including several growth factors. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation.

Overview

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 Tie2 Stabilize vessels
PDGF (BB-homodimer) and PDGFR recruit smooth muscle cells
TGF-β, endoglin and TGF-β receptors ↑extracellular matrix production
MCP-1
Integrins αVβ3, αVβ5 (?[9]) 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
NOS and COX-2
AC133 regulates angioblast differentiation
Id1/Id3 Regulates endothalial transdifferentiation

FGF

Further information: Fibroblast Growth Factor

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[10]. Fibroblast growth factors, or FGFs, are a family of Growth factors involved in Angiogenesis, Wound healing, and embryonic development Vascular endothelial growth factor ( VEGF) a sub-family of Growth factors, more specifically of Platelet-derived growth factor family of cystine-knot growth VEGF receptors are receptors for Vascular Endothelial Growth Factor (VEGF Neuropilin 1, also known as NRP1, is a human Gene. This is one of two human Neuropilins Angiopoietin 1 is a type of Angiopoietin and is encoded In Molecular biology, Platelet-derived growth factor ( PDGF) is one of the numerous Growth factors or Proteins that regulate cell growth The platelet-derived growth factors PDGF-A and -B have for already more than 30 years been recognized as important factors regulating Cell proliferation, Cellular Smooth muscle is a type of non- Striated muscle, found within the Tunica media layer of large and small Arteries and Veins, the bladder Transforming growth factor beta (TGF-β controls proliferation, Cellular differentiation, and other functions in most cells Endoglin is a type I membrane Glycoprotein located on cell surfaces and is part of the TGF beta receptor complex Transforming growth factor (sometimes referred to as Tumor growth factor, or TGF) is used to describe two classes of Polypeptide Growth factors In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells For the ICAO airport code see Candle Lake Airpark, for the diradical compound see Dichlorocarbene. αVβ3 is a type of Integrin that is a receptor for Vitronectin. αVβ5 is a type of Integrin that binds to Matrix macromolecules and Proteinases and thereby stimulates Angiogenesis. α5β1 is an Integrin that binds to Matrix macromolecules and Proteinases and thereby stimulates Angiogenesis. In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells A protease is any Enzyme that conducts Proteolysis, that is begins protein Catabolism by Hydrolysis of the Peptide bonds that link Cadherin 5 type 2 or VE-cadherin (vascular epithelium also known as CD144 ( C luster of D ifferentiation 144) is a type of Cadherin CD31 is a Cluster of differentiation Molecule. It is also called PECAM-1 for platelet endothelial cell adhesion molecule A cell junction is a structure within a tissue of a Multicellular Organism. In Molecular biology, ephrins and Eph receptors are components of Cell signaling pathways involved in Animal development A plasminogen activator is a Serine protease which converts Plasminogen to plasmin thus promoting Fibrinolysis. In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells Plasminogen activator inhibitor-1 is the principal inhibitor of Tissue plasminogen activator (tPA and Urokinase (uPA the activators of Plasminogen Nitric oxide synthases ((NOSs are present among Eukaryotic enzymes as dimeric calmodulin-dependent or calmodulin-containing Cytochrome p450 -like Hemoprotein that cyclooxygenase Prostaglandin-endoperoxide synthase 2 (prostaglandin G/H synthase and cyclooxygenase, also known as PTGS2, is a human Gene. Blood vessels first make their appearance in several scattered vascular areas that are developed simultaneously between the Entoderm and the Mesoderm of the Yolk-sac ID3 is a Metadata container most often used in conjunction with the MP3 Audio file format. Transdifferentiation in Biology takes place when a non- Stem cell transforms into a different type of cell, or when an already differentiated Fibroblast growth factors, or FGFs, are a family of Growth factors involved in Angiogenesis, Wound healing, and embryonic development Most are 16-18 kDa single chain peptides 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 comprised 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 up regulation of FGF-receptors occurs[11]. 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[6][12].

Until now (2007), three human clinical trials have been successfully completed with FGF-1 in which the angiogenic protein was injected directly into the damaged heart muscle[4][13][14][7]. Also, one additional human FGF-1 trial has been completed to promote wound healing in diabetics with chronic wounds.

Besides FGF-1, one of the most important functions of also 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. Basic fibroblast growth factor, also known as bFGF or FGF2, is a member of the Fibroblast growth factor family FGF-2 is a more potent angiogenic factor than VEGF or PDGF (platelet-derived growth factor), however, less potent than FGF-1. In Molecular biology, Platelet-derived growth factor ( PDGF) is one of the numerous Growth factors or Proteins that regulate cell growth 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.

VEGF

VEGF (Vascular Endothelial Growth Factor) has been demonstrated to be a major contributor to angiogenesis, increasing the number of capillaries in a given network. Vascular endothelial growth factor ( VEGF) a sub-family of Growth factors, more specifically of Platelet-derived growth factor family of cystine-knot growth Initial in vitro studies demonstrated that 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[15]. Basic fibroblast growth factor, also known as bFGF or FGF2, is a member of the Fibroblast growth factor family 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[16][17][18][19]. 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. [8] VEGF causes a massive signaling cascade in endothelial cells. Vascular endothelial growth factor ( VEGF) a sub-family of Growth factors, more specifically of Platelet-derived growth factor family of cystine-knot growth The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the 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, producting 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. Messenger ribonucleic acid ( mRNA) is a molecule of RNA encoding a chemical "blueprint" for a Protein product The increase in receptor production means that 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 that there are other factors involved in the angiogenic response. [8]

Angiopoietins

The angiopoietins, Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse knock out studies [20]. The angiopoietins are Protein Growth factors that promote Angiogenesis, the formation of blood vessels 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. Angiopoietin 1 is a type of Angiopoietin and is encoded Angiopoietin 2, also known as ANGPT2, is a human These receptors are tyrosine kinases. A tyrosine kinase is an Enzyme that can transfer a Phosphate group from ATP to a Tyrosine residue in a Protein. Thus, they can initiate cell signaling when ligand binding causes a dimerization that initiates phosphorylation on key tyrosines. Cell signaling is part of a Complex system of Communication that governs basic cellular activities and coordinates cell actions Phosphorylation is the addition of a Phosphate (PO4 group to a Protein molecule or a small molecule

MMP

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. The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the Inhibition of MMPs prevents the formation of new capillaries[21]. Capillaries are the smallest of a body's Blood vessels measuring 5-10 μm in diameter which connect Arterioles and Venules and enable the interchange These enzymes are highly regulated during the vessel formation process because destruction of the extracellular matrix would decrease the integrity of the microvasculature. Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins In Biology, the extracellular matrix ( ECM) is the Extracellular part of animal tissue that usually provides structural support to the cells [8]

DII4

DII4 (Delta-like ligand 4), is a recently discovered protein growth factor with important angiogenic properties similar to VEGF. The term growth factor refers to a naturally occurring Protein capable of stimulating cellular growth proliferation and Cellular differentiation. [22]. Dll4 is a transmembrane ligand, for the Notch family of receptors.

Chemical inhibition

Main article: Angiogenesis inhibitor

Angiogenesis inhibitor can be endogenous or come from outside as drug or a dietary component. An angiogenesis inhibitor is a substance that inhibits Angiogenesis (the growth of new blood vessels Medication, also referred to as medicine, can be loosely defined as any substance intended for use in the diagnosis cure mitigation treatment or prevention of disease This article is primarily about the human diet For a discussion of animal diets see List of feeding behaviours.

Applications

Tumor angiogenesis

Cancer cells are cells that have lost their ability to divide in a controlled fashion. Cancer (medical term Malignant Neoplasm) is a class of Diseases in which a group of cells display uncontrolled The cell is the structural and functional unit of all known living Organisms It is the smallest unit of an organism that is classified as living and is often called A tumor consists of a population of rapidly dividing and growing cancer cells. Mutations rapidly accrue within the population. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism These mutations (variation) allow the cancer cells (or sub-populations of cancer cells within a tumor) to develop drug resistance and escape therapy. Drug resistance is the reduction in effectiveness of a drug in curing a disease or improving a patient's symptoms Tumors cannot grow beyond a certain size, generally 1-2 mm³, due to a lack of oxygen and other essential nutrients.

Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e. g. Vascular Endothelial Growth Factor or VEGF). Vascular endothelial growth factor ( VEGF) a sub-family of Growth factors, more specifically of Platelet-derived growth factor family of cystine-knot growth 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. Basic fibroblast growth factor, also known as bFGF or FGF2, is a member of the Fibroblast growth factor family On 18 July 2007 it was discovered that cancerous cells stop producing the anti-VEGF enzyme PKG. Events 390 BC - Roman - Gaulish Wars Battle of the Allia - a Roman army is defeated by raiding Gauls, Year 2007 ( MMVII) was a Common year starting on Monday of the Gregorian calendar in the 21st century. cGMP-dependent protein kinase or Protein Kinase G (PKG is a Serine/threonine-specific protein kinase that is activated by cGMP. In normal cells (but not in cancerous ones), PKG apparently limits beta-catenin which solicits angiogenesis. Beta-catenin is a subunit of the Cadherin protein complex In Drosophila, the homologous protein is called armadillo. [23] Other clinicians believe that angiogenesis really serves as a waste pathway, taking away the biological end products put out 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. Metastasis ( Greek: displacement μετά=next + στάσις=placement, plural metastases) sometimes abbreviated mets, 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 that the blood vessel in a given solid tumor may in fact be mosaic vessels, comprised of endothelial cells and tumor cells. The endothelium is the thin layer of cells that line the interior surface of Blood vessels forming an interface between circulating Blood in the This mosaicity allows for substantial shedding of tumor cells into the vasculature. The subsequent growth of such metastases will also require a supply of nutrients and oxygen or a waste disposal pathway. Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the

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. Recent studies by Klagsbrun, et al. have shown, however, that endothelial cells growing within tumors do carry genetic abnormalities. Thus, tumor vessels have the theoretical potential for developing acquired resistance to drugs. This is a new area of angiogenesis research being actively pursued.

Formation of tumor blood vessels

Tumour blood vessels have perivascular detachment, vessel dilation, and irregular shape. It is believed that tumor blood vessels are not smooth like normal tissues and are not ordered sufficiently to give oxygen to all of the tissues. [1] Endothelial precursor cells are organized from bone marrow, which are than integrated into the growing blood vessels. [2] Then the endothelial cells differentiate and migrate into perivascular space, to form tumour cells. Vascular endothelial growth factor (VEGF) plays a crucial role in the formation of blood vessel that lead to tumor growth, which allows the vessel to expand. It is called sprouting angiogenesis.

References:

1. Brown J. M. , and Giaccia A. J. , The Unique Physiology of Solid Tumors: Opportunities (and Problems) for Cancer Therapy. Cancer Research 58, 1408-1416, April 1, 1998 American Association for Cancer Research

2. Benjamin L. E. , and Bergers G. , Angiogenesis: Tumorigenesis and the angiogenic switch. Nature Reviews Cancer 3, 401-410 (June 2003

3. Rafii, S. et al. Efficient mobilization and recruitment of marrow-derived endothelial and hematopoietic stem cells by adenoviral vectors expressing angiogenic factors. Gene Ther. 9, 631–641 (2002)

Angiogenesis research is a cutting edge field in cancer research, and recent evidence also suggests that traditional therapies, such as radiation therapy, may actually work in part by targeting the genomically stable endothelial cell compartment, rather than the genomically unstable tumor cell compartment. Cancer research is research into Cancer in order to identify causes and develop strategies for prevention diagnosis treatments and cure New blood vessel formation is a relatively fragile process, subject to disruptive interference at several levels. In short, the therapy is the selection agent which is being used to kill a cell compartment. Tumor cells evolve resistance rapidly due to rapid generation time (days) and genomic instability (variation), whereas endothelial cells are a good target because of a long generation time (months) and genomic stability (low variation).

This is an example of selection in action at the cellular level, using a selection pressure to target and differentiate between varying populations of cells. In the context of Evolution, certain traits or Alleles of a Species may be subject to selection The end result is the extinction of one species or population of cells (endothelial cells), followed by the collapse of the ecosystem (the tumor) due either to nutrient deprivation or self-pollution from the destruction of necessary waste pathways. In Biology and Ecology, extinction is the cessation of existence of a Species or group of taxa. An ecosystem is a natural unit consisting of all plants animals and micro-organisms( Biotic factors in an area functioning together with all of the non-living physical (

Angiogenesis-based tumour therapy relies on natural and synthetic angiogenesis inhibitors like angiostatin, endostatin and tumstatin. An angiogenesis inhibitor is a substance that inhibits Angiogenesis (the growth of new blood vessels Angiostatin is a naturally occurring Protein found in several animal species including humans Endostatin is a naturally-occurring 20-kDa C-terminal fragment derived from Type XVIII collagen. These are proteins that mainly originate as specific fragments pre-existing structural proteins like collagen or plasminogen. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Collagen is the main Protein of Connective tissue in Animals and the most abundant protein in Mammals making up about 50% of the whole-body protein Plasmin is an important Enzyme ( present in Blood that degrades many Blood plasma proteins most notable Fibrin clots The degradation

Recently, the 1st FDA-approved therapy targeted at angiogenesis in cancer came on the market in the US. This is a monoclonal antibody directed against an isoform of VEGF. Monoclonal antibodies ( mAb or moAb) are monospecific antibodies that are identical because they are produced by one type of immune cell The commercial name of this antibody is Avastin, and the therapy has been approved for use in colorectal cancer in combination with established chemotherapy. Bevacizumab (Avastin Genentech/Roche is a Monoclonal antibody against Vascular endothelial growth factor (VEGF Colorectal cancer, also called colon cancer or large bowel cancer, includes Cancerous growths in the colon, Rectum and

Angiogenesis for cardiovascular disease

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[6]. A large number of pre-clinical 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. However, a decade of clinical testing both gene- and protein-based therapies designed to stimulate angiogenesis in underperfused tissues and organs, has led from one disappointment to another. Although all of these pre-clinical 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.

If one reviews in detail the various published angiogenesis clinical trials, it can be realized that most of these trials had success in achieving various secondary or supportive endpoints, but failed when attempting to demonstrate a statistically significant improvement in exercise performance, typically done by a treadmill exercise test[24]. Perhaps the greatest reason for these trials’ failure to achieve success is the high occurrence of the “placebo effect” in studies employing treadmill exercise test readout. Thus, even though a majority of the treated patients in these trials experience relief of such clinical symptoms such as chest pain (angina), and generally performed better on most efficacy readouts, there were enough “responders” in the blinded placebo groups to render the trial inconclusive. In addition to the placebo effect, more recent animal studies have also highlighted various factors that may inhibit an angiogenesis response including certain drugs, smoking, and hypercholesterolemia.

Although shown to be relatively safe therapies, not one angiogenic therapeutic has yet made it through the gauntlet of clinical testing required for drug approval. By capitalizing on the large database of what did and did not work in previous clinical trials, results from more recent studies with redesigned clinical protocols give renewed hope that angiogenesis therapy will be a treatment choice for sufferers of cardiovascular disease resulting from occluded and/or stenotic vessels.

Early clinical studies with protein-based therapeutics largely focused on the intravenous or intracoronary administration of a particular growth factor to stimulate angiogenesis in the affected tissue or organ. Most of these trials did not achieve statistically significant improvements in their clinical endpoints. This ultimately led to an abandonment of this approach and a widespread belief in the field that protein therapy, especially with a single agent, was not a viable option to treat ischemic cardiovascular disease. However, the failure of gene- or cell-based therapy to deliver, as of yet, a suitable treatment choice for diseases resulting from poor blood flow, has led to a resurgence of interest in returning to protein-based therapy to stimulate angiogenesis.

These failures suggested that either these are the wrong molecular targets to induce neovascularization, that they can only be effectively utilized 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. Presentation is the process of showing and explaining the content of a topic to an audience 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[25]. In Chemistry, concentration is the measure of how much of a given substance there is mixed with another substance Space is the extent within which Matter is physically extended and objects and Events have positions relative to one another

Lessons learned from earlier protein-based studies, which indicated that intravenous or intracoronary delivery of the protein was not efficacious, have led to completed and ongoing clinical trials in which the angiogenic protein is injected directly into the beating ischemic heart.

Such localized administration of the potent angiogenic growth factor, human FGF-1, has recently given promising results in clinical trials in no-option heart patients[26][27]. Angiogenesis was documented by angiographically visible “blushing”, and functional exercise tests were also performed on a subset of patients. The attractiveness of protein therapy is that large amounts of the therapeutic agent can be injected into the ischemic area of interest, to pharmacologically start the process of blood vessel growth and collateral arteries’ formation[7]. In addition, from pharmacokinetic data collected from the recent FGF-1 studies in the human heart, it appears that FGF-1, once it exits the heart is cleared in less than three hours from the circulation. This would presumably prevent FGF-1 from stimulating unwanted angiogenesis in other tissues of the bodies where it could potentially cause harm, such as the retina and in the kidneys. No serious adverse events have yet to be noted in any of the completed or ongoing clinical trials in which the FGF-1 protein is utilized as the therapeutic agent tom stimulate angiogenesis[7][28].

Image:Angiogenesis_Human_Heart_1.jpg

Left: Angiographic "blushing" following FGF-1 injection into the human heart. Right, measurements of pixel density in angiograms ("gray-value-analysis") indicating a threefold increase in vessel density in the treated human myocardium (3 months & 3 years).

Image:Angiogenesis_Human_Heart_2.jpg

Improvement in myocardial perfusion (blood supply) after FGF-1 treatment as demonstrated by SPECT imaging (single photon emission computed tomography).

Exercise

Angiogenesis is generally associated with aerobic exercise and endurance exercise. Aerobic exercise refers to Exercise that involves or improves oxygen consumption by the body 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. Arteriogenesis refers to an increase in the Diameter of existing arterial vessels 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 exists to suggest that increased capillarity is required in endurance exercise to increase the maximum oxygen delivery. [8]

Macular degeneration

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. Macular degeneration is a medical condition usually of older adults which results in a loss of vision in the center of the visual field (the Macula) because Since the increase in angiogenesis also causes edema, blood and other retinal fluids leak into the retina causing loss of vision. Oedema (or Edema in American English formerly known as dropsy or hydropsy, is the increase of Interstitial fluid in any organ &mdash swelling A novel treatment of this disease is to use a VEGF inhibiting siRNA to stop the main signaling cascade for angiogenesis. Small interfering RNA ( siRNA) sometimes known as short interfering RNA or silencing RNA, is a class of 20-25 Nucleotide -long double-stranded

See also

References

  1. ^ Burri, PH (2004). Arteriogenesis refers to an increase in the Diameter of existing arterial vessels Aerobic exercise refers to Exercise that involves or improves oxygen consumption by the body "Intussusceptive angiogenesis: its emergence, its characteristics, and its significance. ". Dev Dyn. 231 (3): 474-88.  
  2. ^ Folkman, J, Klagsbrun, M: Angiogenetic factors. Science 235: 442-447, 1987
  3. ^ Folkman J. Fighting cancer by attacking its blood supply. Sci Am. 275:150 –154, 1996
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  5. ^ Folkman, J. : Angiogenic therapy of the heart. Circulation 97: 628-629, 1998
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  9. ^ Perhaps an inhibitor of angiogenesis: Endothelial integrins and angiogenesis: not so simple anymore
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  16. ^ Ding, Y. H. , Luan, X. D. , Li, J. , Rafols, J. A. , Guthinkonda, M. , & Diaz, F. G. et al. Exercise-induced overexpression of angiogenic factors and reduction of ischemia/reperfusion injury in stroke. Curr Neurovasc Res 1: 411-20, 2004
  17. ^ Gavin, T. P. , Robinson, C. B. , Yeager, R. C. , England, J. A. , Nifong, L. W. , & Hickner, R. C. Angiogenic growth factor response to acute systemic exercise in human skeletal muscle. J App Physiol 96: 19-24, 2004
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  23. ^ Enzyme eliminated by cancer cells holds promise for cancer treatment
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  27. ^ Wagoner, L. E, Snavely, D. D. , Conway, G. A. , Hauntz, E. A. , Merrill, W. H. : Intramyocardial injection of fibroblast growth factor-1 for treatment of refractory angina pectoris: the initial US experience. Circulation; 110: 395, 2004
  28. ^ Stegmann TJ. New Vessels for the Heart. Angiogenesis as New Treatment for Coronary Heart Disease: The Story of its Discovery and Development. Henderson, Nevada: CardioVascular BioTherapeutics Inc. , 2004

External links

Dictionary

angiogenesis

-noun

  1. The formation and development of new blood vessels.
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