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Angiogenesis is the physiological process through which new
blood vessel
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away ...
s form from pre-existing vessels,
formed in the earlier stage of
vasculogenesis
Vasculogenesis is the process of blood vessel formation, 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 ang ...
. Angiogenesis continues the growth of the
vasculature
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
by processes of sprouting and splitting.
Vasculogenesis is the
embryonic
Embryonic may refer to:
*Of or relating to an embryo
* ''Embryonic'' (album), a 2009 studio album by the Flaming Lips
*''Embryonics
''Embryonics'' is a double-CD compilation of tracks by the Australian progressive metal band, Alchemist. It w ...
formation of
endothelial
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
cells from
mesoderm
The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical E ...
cell precursors,
and from
neovascularization
Neovascularization is the natural formation of new blood vessels ('' neo-'' + '' vascular'' + '' -ization''), usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circu ...
, although discussions are not always precise (especially in older texts). The first vessels in the developing
embryo
An embryo is an initial stage of development of a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male spe ...
form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during
development
Development or developing may refer to:
Arts
*Development hell, when a project is stuck in development
*Filmmaking, development phase, including finance and budgeting
*Development (music), the process thematic material is reshaped
* Photograph ...
and in disease.
Angiogenesis is a normal and vital process in growth and development, as well as in
wound healing
Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue.
In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
and in the formation of
granulation tissue
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 ...
. However, it is also a fundamental step in the transition of
tumor
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
s from a benign state to a
malignant
Malignancy () is the tendency of a medical condition to become progressively worse.
Malignancy is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous ''benign'' tumor in that a malignancy is not s ...
one, leading to the use of
angiogenesis inhibitor 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 drugs, pharmaceuti ...
s in the treatment of
cancer
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal b ...
.
The essential role of angiogenesis in tumor growth was first proposed in 1971 by
Judah Folkman
Moses Judah Folkman (February 24, 1933 – January 14, 2008) was an American medical scientist best known for his research on tumor angiogenesis, the process by which a tumor attracts blood vessels to nourish itself and sustain its existence. He ...
, who described tumors as "hot and bloody,"
illustrating that, at least for many tumor types, flush
perfusion
Perfusion is the passage of fluid through the circulatory system or lymphatic system to an organ or a tissue, usually referring to the delivery of blood to a capillary bed in tissue. Perfusion is measured as the rate at which blood is deliver ...
and even
hyperemia
Hyperaemia (also hyperemia) is the increase of blood flow to different tissues in the body. It can have medical implications but is also a regulatory response, allowing change in blood supply to different tissues through vasodilation. Clinically, ...
are characteristic.
Types
Sprouting angiogenesis
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
Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the ''VEGFA'' gene.
Function
This gene is a member of the platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) family and encod ...
) which is a proangiogenic growth factor. These biological signals activate
receptor
Receptor may refer to:
* Sensory receptor, in physiology, any structure which, on receiving environmental stimuli, produces an informative nerve impulse
*Receptor (biochemistry), in biochemistry, a protein molecule that receives and responds to a ...
s on
endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s present in pre-existing blood vessels. Second, the activated endothelial cells, also known as tip cells, begin to release
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s called
protease
A protease (also called a peptidase, proteinase, or proteolytic enzyme) is an enzyme that catalyzes (increases reaction rate or "speeds up") proteolysis, breaking down proteins into smaller polypeptides or single amino acids, and spurring the ...
s that degrade the
basement membrane
The basement membrane is a thin, pliable sheet-like type of extracellular matrix that provides cell and tissue support and acts as a platform for complex signalling. The basement membrane sits between Epithelium, epithelial tissues including mesot ...
to allow endothelial cells to escape from the original (parent) vessel walls. The
endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s then
proliferate into the surrounding
matrix
Matrix most commonly refers to:
* ''The Matrix'' (franchise), an American media franchise
** ''The Matrix'', a 1999 science-fiction action film
** "The Matrix", a fictional setting, a virtual reality environment, within ''The Matrix'' (franchis ...
and form solid sprouts connecting neighboring vessels. The cells that are proliferating are located behind the tip cells and are known as stalk cells. The proliferation of these cells allows the capillary sprout to grow in length simultaneously.
As sprouts extend toward the source of the angiogenic stimulus, endothelial cells migrate in
tandem
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.
The original use of the term in English was in ''tandem harness'', which is used for two ...
, using adhesion molecules called
integrin
Integrins are transmembrane receptors that facilitate cell-cell and cell-extracellular matrix (ECM) adhesion. Upon ligand binding, integrins activate signal transduction pathways that mediate cellular signals such as regulation of the cell cycle, ...
s. 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
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
. It is markedly different from splitting angiogenesis because it forms entirely new vessels as opposed to splitting existing vessels.
Intussusceptive angiogenesis
Intussusceptive angiogenesis
Intussusceptive angiogenesis also known as splitting angiogenesis, is a type of angiogenesis, the process whereby a new blood vessel is created. By intussusception a new blood vessel is created by splitting of an existing blood vessel in two. In ...
, also known as ''splitting angiogenesis'', is the formation of a new blood vessel by splitting an existing blood vessel into two.
Intussusception was first observed in
neonatal
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
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
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
cell junction
Cell junctions (or intercellular bridges) are a class of cellular structures consisting of multiprotein complexes that provide contact or adhesion between neighboring cells or between a cell and the extracellular matrix in animals. They also main ...
s are reorganized and the vessel
bilayer
A bilayer is a double layer of closely packed atoms or molecules.
The properties of bilayers are often studied in condensed matter physics, particularly in the context of semiconductor devices, where two distinct materials are united to form jun ...
is
perforated
A perforation is a small hole in a thin material or web. There is usually more than one perforation in an organized fashion, where all of the holes collectively are called a ''perforation''. The process of creating perforations is called perfor ...
to allow
growth factors
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
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
pericyte
Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood ca ...
s and
myofibroblast
A myofibroblast is a cell phenotype that was first described as being in a state between a fibroblast and a smooth muscle cell.
Structure
Myofibroblasts are contractile web-like fusiform cells that are identifiable by their expression of α-sm ...
s. These cells begin laying
collagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
fibers into the core to provide an
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
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
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
without a corresponding increase in the number of
endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s. This is especially important in embryonic development as there are not enough resources to create a rich
microvasculature
The microcirculation is the circulation of the blood in the smallest blood vessels, the microvessels of the microvasculature present within organ tissues. The microvessels include terminal arterioles, metarterioles, capillaries, and venules. ...
with new cells every time a new vessel develops.
Physiology
Mechanical stimulation
Mechanical stimulation of angiogenesis is not well characterized. There is a significant amount of controversy with regard to
shear stress
Shear stress, often denoted by (Greek: tau), is the component of stress coplanar with a material cross section. It arises from the shear force, the component of force vector parallel to the material cross section. ''Normal stress'', on the ot ...
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
Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
during exercise. Nitric oxide results in vasodilation of blood vessels.
Chemical stimulation
Chemical stimulation of angiogenesis is performed by various angiogenic proteins e.g. integrins and prostaglandins, including several
growth factor
A growth factor is a naturally occurring substance capable of stimulating cell proliferation, wound healing, and occasionally cellular differentiation. Usually it is a secreted protein or a steroid hormone. Growth factors are important for regu ...
s e.g. VEGF, FGF.
Overview
FGF
The
fibroblast growth factor
Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...
(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
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(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
Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...
) 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
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 v ...
); 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.
VEGF
Vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
(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
Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...
, 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
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
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
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
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.
Angiopoietins
The
angiopoietins
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 pre ...
, Ang1 and Ang2, are required for the formation of mature blood vessels, as demonstrated by mouse
knock out
A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several full-contact combat sports, such as boxing, kickboxing, muay thai, mixed martial arts, karate, some forms of taekwondo and other sports involving striking, a ...
studies.
Ang1
Angiopoietin 1 is a type of angiopoietin and is encoded by the gene ANGPT1.
Angiopoietins are proteins with important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific ty ...
and
Ang2
__NOTOC__
Angiopoietin-2 is a protein that in humans is encoded by the ''ANGPT2'' gene.
Naturally occurring antagonist for both ANGPT1
Angiopoietin 1 is a type of angiopoietin and is encoded by the gene ANGPT1.
Angiopoietins are proteins w ...
are protein growth factors which act by binding their receptors,
Tie-1
Tyrosine kinase with immunoglobulin-like and EGF-like domains 1 also known as TIE1 is an angiopoietin receptor which in humans is encoded by the ''TIE1'' gene.
Function
TIE1 is a cell surface protein expressed exclusively in endothelial cells, ...
and
Tie-2
The angiopoietin receptors are receptors that bind angiopoietin.
TIE-1 and TIE-2 comprise the cell-surface receptors that bind and are activated by the angiopoietins, (Ang1, Ang2, Ang3, Ang4). The angiopoietins are protein growth factors r ...
; while this is somewhat controversial, it seems that cell signals are transmitted mostly by
Tie-2
The angiopoietin receptors are receptors that bind angiopoietin.
TIE-1 and TIE-2 comprise the cell-surface receptors that bind and are activated by the angiopoietins, (Ang1, Ang2, Ang3, Ang4). The angiopoietins are protein growth factors r ...
; though some papers show physiologic signaling via
Tie-1
Tyrosine kinase with immunoglobulin-like and EGF-like domains 1 also known as TIE1 is an angiopoietin receptor which in humans is encoded by the ''TIE1'' gene.
Function
TIE1 is a cell surface protein expressed exclusively in endothelial cells, ...
as well. These receptors are
tyrosine kinases
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to the tyrosine residues of specific proteins inside a cell. It functions as an "on" or "off" switch in many cellular functions.
Tyrosine kinases belong to a larger cla ...
. Thus, they can initiate
cell signaling
In biology, cell signaling (cell signalling in British English) or cell communication is the ability of a cell to receive, process, and transmit signals with its environment and with itself. Cell signaling is a fundamental property of all cellula ...
when ligand binding causes a dimerization that initiates
phosphorylation
In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
on key tyrosines.
MMP
Another major contributor to angiogenesis is
matrix metalloproteinase
Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs b ...
(MMP). MMPs help degrade the proteins that keep the vessel walls solid. This
proteolysis
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called protease ...
allows the
endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
s to escape into the interstitial matrix as seen in sprouting angiogenesis. Inhibition of MMPs prevents the formation of new
capillaries
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
.
These
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
s are highly regulated during the vessel formation process because destruction of the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide stru ...
would decrease the integrity of the microvasculature.
Dll4
Delta-like ligand 4 (Dll4) is a protein with a negative regulatory effect on angiogenesis. Dll4 is a transmembrane ligand, for the
notch family of receptors
The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmemb ...
. 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
Class 3 semaphorins (SEMA3s) regulate angiogenesis by modulating
endothelial cell
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
adhesion, migration, proliferation, survival and the recruitment of
pericyte
Pericytes (previously known as Rouget cells) are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. Pericytes are embedded in the basement membrane of blood ca ...
s.
Furthermore,
semaphorin
Semaphorins are a class of secreted and membrane proteins that were originally identified as axonal growth cone guidance molecules. They primarily act as short-range inhibitory signals and signal through multimeric receptor complexes. Semaphorins ...
s can interfere with VEGF-mediated angiogenesis since both SEMA3s and
VEGF-A
Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the ''VEGFA'' gene.
Function
This gene is a member of the platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF) family and encod ...
compete for
neuropilin
Neuropilin is a protein receptor active in neurons.
There are two forms of Neuropilins, NRP-1 and NRP-2. Neuropilins are transmembrane glycoproteins, first documented to regulate neurogenesis and angiogenesis by complexing with Plexin recepto ...
receptor binding at endothelial cells.
The relative expression levels of SEMA3s and VEGF-A may therefore be important for angiogenesis.
Chemical inhibition
An
angiogenesis inhibitor 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 drugs, pharmaceuti ...
can be endogenous or come from outside as
drug
A drug is any chemical substance that causes a change in an organism's physiology or psychology when consumed. Drugs are typically distinguished from food and substances that provide nutritional support. Consumption of drugs can be via insuffla ...
or a
dietary component.
Application in medicine
Angiogenesis as a therapeutic target
Angiogenesis may be a target for combating diseases such as
heart disease
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, hea ...
characterized by either poor vascularisation or abnormal vasculature. Application of specific compounds that may inhibit or induce the creation of new
blood vessels
The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
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
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
, 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
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
and nutrients to proliferate, pro-angiogenic therapies are being explored as options to treat
cardiovascular diseases
Cardiovascular disease (CVD) is a class of diseases that involve the heart or blood vessels. CVD includes coronary artery diseases (CAD) such as angina and myocardial infarction (commonly known as a heart attack). Other CVDs include stroke, ...
, the number one cause of death in the
Western world
The Western world, also known as the West, primarily refers to the various nations and state (polity), states in the regions of Europe, North America, and Oceania. . 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
In pharmacology, the term mechanism of action (MOA) refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect. A mechanism of action usually includes mention of the specific molecular targe ...
, pro-angiogenic methods can be differentiated into three main categories:
gene therapy
Gene therapy is a medical field which focuses on the genetic modification of cells to produce a therapeutic effect or the treatment of disease by repairing or reconstructing defective genetic material. The first attempt at modifying human DN ...
, targeting genes of interest for amplification or inhibition;
protein replacement therapy Protein replacement therapy is a medical treatment that supplements or replaces a protein in patients in whom that particular protein is deficient or absent. There have been significant advances in this treatment. PRT is being tested in clinical tr ...
, which primarily manipulates angiogenic growth factors like
FGF-1
Fibroblast growth factor 1, (FGF-1) also known as acidic fibroblast growth factor (aFGF), is a growth factor and signaling protein encoded by the ''FGF1'' gene. It is synthesized as a 155 amino acid polypeptide, whose mature form is a non-glycos ...
or
vascular endothelial growth factor
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
, 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
Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response in the body of a human or other animal. It may be wanted or unwanted:
* Wanted immunogenicity typically relates to vaccines, where the injectio ...
, inflammatory responses, and
oncogenesis
Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abno ...
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
Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...
, 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.
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.
Tumor angiogenesis
![Diagram showing why cancer cells need their own blood supply](https://upload.wikimedia.org/wikipedia/commons/8/82/Diagram_showing_why_cancer_cells_need_their_own_blood_supply.svg)
Cancer cells are cells that have lost their ability to divide in a controlled fashion. A
malignant tumor
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread. Possible signs and symptoms include a lump, abnormal ble ...
consists of a population of rapidly dividing and growing cancer cells that progressively accrues
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...
s. 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 mm
3).
Tumors induce blood vessel growth (angiogenesis) by secreting various growth factors (e.g.
VEGF
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
) and proteins. Growth factors such as
bFGF
Fibroblast growth factor 2, also known as basic fibroblast growth factor (bFGF) and FGF-β, is a growth factor and signaling protein encoded by the ''FGF2'' gene. It binds to and exerts effects via specific fibroblast growth factor receptor ''(FG ...
and
VEGF
Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...
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
Metastasis is a pathogenic agent's spread from an initial or primary site to a different or secondary site within the host's body; the term is typically used when referring to metastasis by a cancerous tumor. The newly pathological sites, then, ...
.
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
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
and tumor cells.
This mosaicity allows for substantial shedding of tumor cells into the vasculature, possibly contributing to the appearance of
circulating tumor cell A circulating tumor cell (CTC) is a cell that has shed into the vasculature or lymphatics from a primary tumor and is carried around the body in the blood circulation. CTCs can extravasate and become ''seeds'' for the subsequent growth of additional ...
s in the peripheral blood of patients with malignancies. The subsequent growth of such metastases will also require a supply of nutrients and
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements as wel ...
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
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
directed at cancer cells, which rapidly mutate and acquire
drug resistance
Drug resistance is the reduction in effectiveness of a medication such as an antimicrobial or an antineoplastic in treating a disease or condition. The term is used in the context of resistance that pathogens or cancers have "acquired", that is, ...
to treatment. For this reason,
endothelial cells
The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...
are thought to be an ideal target for therapies directed against them.
Formation of tumor blood vessels
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
Proteolysis is the breakdown of proteins into smaller polypeptides or amino acids. Uncatalysed, the hydrolysis of peptide bonds is extremely slow, taking hundreds of years. Proteolysis is typically catalysed by cellular enzymes called proteases, ...
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 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 ''neoangiogenesis'': 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 with 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
A presentation conveys information from a speaker to an audience. Presentations are typically demonstrations, introduction, lecture, or speech meant to inform, persuade, inspire, motivate, build goodwill, or present a new idea/product. Presenta ...
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
In chemistry, concentration is the abundance of a constituent divided by the total volume of a mixture. Several types of mathematical description can be distinguished: '' mass concentration'', ''molar concentration'', ''number concentration'', an ...
,
spatial and
temporal profiles, and their simultaneous or sequential presentation with other appropriate factors.
Exercise
Angiogenesis is generally associated with
aerobic exercise
Aerobic exercise (also known as endurance activities, cardio or cardio-respiratory exercise) is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, inv ...
and
endurance exercise
Endurance training is the act of exercising to increase endurance. The term endurance training generally refers to training the aerobic system as opposed to the anaerobic system. The need for endurance in sports is often predicated as the need o ...
. While
arteriogenesis
Arteriogenesis refers to an increase in the diameter of existing arterial vessels.
Mechanical Stimulation
Mechanically, arteriogenesis is linked to elevated pressure, which increases radial wall stress, and elevated flow, which increases endotheli ...
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.
Macular degeneration
Overexpression of VEGF causes increased permeability in blood vessels in addition to stimulating angiogenesis. In wet
macular degeneration
Macular degeneration, also known as age-related macular degeneration (AMD or ARMD), is a medical condition which may result in blurred or no vision in the center of the visual field. Early on there are often no symptoms. Over time, however, som ...
, VEGF causes proliferation of capillaries into the retina. Since the increase in angiogenesis also causes
edema
Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's Tissue (biology), tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels t ...
, blood and other retinal fluids leak into the
retina
The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
, causing loss of vision. Anti-angiogenic drugs targeting the VEGF pathways are now used successfully to treat this type of macular degeneration
Tissue engineered constructs
Angiogenesis of vessels from the host body into an implanted tissue engineered constructs is essential. Successful integration 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.
Quantification
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.
See also
*
Aerobic exercise
Aerobic exercise (also known as endurance activities, cardio or cardio-respiratory exercise) is physical exercise of low to high intensity that depends primarily on the aerobic energy-generating process. "Aerobic" is defined as "relating to, inv ...
*
The Angiogenesis Foundation
The Angiogenesis Foundation, is a United States 501(c)(3) nonprofit organization established in 1994 for the study of angiogenesis. The founders were former students of Dr. Judah Folkman, a pioneer of angiogenesis research.
The foundation focus ...
*
Arteriogenesis
Arteriogenesis refers to an increase in the diameter of existing arterial vessels.
Mechanical Stimulation
Mechanically, arteriogenesis is linked to elevated pressure, which increases radial wall stress, and elevated flow, which increases endotheli ...
*
COL41
*
Neuroangiogenesis 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 ...
*
Proteases in angiogenesis
*
Vasculogenic mimicry
References
External links
Angiogenesis for Heart Disease from Angioplasty.OrgAngiogenesis - The Virtual Library of Biochemistry, Molecular Biology and Cell BiologyNCI Understanding Cancer series on Angiogenesis* A textbook on the topic freely available at NCBI.
Further reading
* Milosevic, V., Edelmann, R.J., Fosse, J.H., Östman, A., Akslen, L.A. (2022).
Molecular Phenotypes of Endothelial Cells in Malignant Tumors. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_3
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Angiology