Angiopoietin
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Angiopoietin is part of a family of vascular
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 ...
that play a role in embryonic and postnatal
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
. Angiopoietin signaling most directly corresponds with angiogenesis, the process by which new arteries and veins form from preexisting blood vessels. Angiogenesis proceeds through sprouting, endothelial cell migration, proliferation, and vessel destabilization and stabilization. They are responsible for assembling and disassembling the endothelial lining of blood vessels. Angiopoietin
cytokines Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling
smooth muscle cells Smooth muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations (''bands'' or ''stripes''). It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit mus ...
surrounding vessels. There are now four identified angiopoietins:
ANGPT1 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 ...
,
ANGPT2 __NOTOC__ Angiopoietin-2 is a protein that in humans is encoded by the ''ANGPT2'' gene. Naturally occurring antagonist for both ANGPT1 and TIE2; expressed only at the sites of vascular remodeling; similar to angiopoietin-1 Function * See A ...
,
ANGPTL3 Angiopoietin-like 3, also known as ANGPTL3, is a protein that in humans is encoded by the ''ANGPTL3'' gene. Function The protein encoded by this gene is a member of the angiopoietin-like family of secreted factors. It is expressed predominantl ...
,
ANGPT4 Angiopoietin-4 is a protein that in humans is encoded by the ''ANGPT4'' gene. Angiopoietins are proteins with important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific ...
. In addition, there are a number of proteins that are closely related to ('like') angiopoietins (
Angiopoietin-related protein 1 Angiopoietin-related protein 1 also known as angiopoietin-3 (ANG-3) is a protein that in humans is encoded by the ANGPTL1 gene. Function Angiopoietins are members of the vascular endothelial growth factor family and the only known growth fac ...
, , , , , , , ). Angiopoietin-1 is critical for vessel maturation, adhesion, migration, and survival. Angiopoietin-2, on the other hand, promotes cell death and disrupts vascularization. Yet, when it is in conjunction with vascular endothelial growth factors, or
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, ...
, it can promote neo-vascularization.


Structure

Structurally, angiopoietins have an
N-terminal The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
super clustering domain, a central coiled domain, a linker region, and a
C-terminal The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein is ...
fibrinogen-related domain responsible for the binding between the ligand and receptor. Angiopoietin-1 encodes a 498 amino acid
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
with a molecular weight of 57 kDa whereas angiopoietin-2 encodes a 496 amino acid polypeptide.


Only clusters/multimers activate receptors

Angiopoietin-1 and angiopoietin-2 can form dimers, trimers, and tetramers. Angiopoietin-1 has the ability to form higher order multimers through its super clustering domain. However, not all of the structures can interact with the tyrosine kinase receptor. The receptor can only be activated at the tetramer level or higher.


Specific mechanisms


Tie pathway

The collective interactions between angiopoietins,
receptor tyrosine kinases Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase ...
,
vascular endothelial growth factors 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 their receptors form the two signaling pathways—
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 ...
. The two receptor pathways are named as a result of their role in mediating cell signals by inducing the
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 ...
of specific tyrosines. This in turn initiates the binding and activation of downstream intracellular
enzymes Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
, a process known as cell signaling.


Tie-2

Tie-2/Ang-1 signaling activates β1-
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, ...
and N-
cadherin Cadherins (named for "calcium-dependent adhesion") are a type of cell adhesion molecule (CAM) that is important in the formation of adherens junctions to allow cells to adhere to each other . Cadherins are a class of type-1 transmembrane proteins, ...
in LSK-Tie2+ cells and promotes
hematopoietic stem cell Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
(HSC) interactions with
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 ...
and its cellular components. Ang-1 promotes quiescence of HSC in vivo. This quiescence or slow cell cycling of HSCs induced by Tie-2/Ang-1 signaling contributes to the maintenance of long-term repopulating ability of HSC and the protection of the HSC compartment from various cellular stresses. Tie-2/Ang-1 signaling plays a critical role in the HSC that is required for the long-term maintenance and survival of HSC in bone marrow. In the
endosteum The endosteum (plural endostea) is a thin vascular membrane of connective tissue that lines the inner surface of the bony tissue that forms the medullary cavity of long bones. This endosteal surface is usually resorbed during long periods of ma ...
, Tie-2/Ang-1 signaling is predominantly expressed by
osteoblastic Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function ...
cells. Although which specific TIE receptors mediate signals downstream of angiogenesis stimulation is highly contested, it is clear that TIE-2 is capable of activation as a result of binding angiopoietins. Angiopoietin proteins 1 through 4 are all
ligands In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's electro ...
for Tie-2 receptors. Tie-1 heterodimerizes with Tie-2 to enhance and modulate signal transduction of Tie-2 for vascular development and maturation. Tyrosine kinase receptors are typically expressed on vascular endothelial cells and specific
macrophages Macrophages (abbreviated as M φ, MΦ or MP) ( el, large eaters, from Greek ''μακρός'' (') = large, ''φαγεῖν'' (') = to eat) are a type of white blood cell of the immune system that engulfs and digests pathogens, such as cancer ce ...
for immune responses. Angiopoietin-1 is a growth factor produced by vascular support cells, specialized pericytes in the kidney, and hepatic stellate cells (ITO) cells in the liver. This growth factor is also a
glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...
and functions as an agonist for the tyrosine receptor found in endothelial cells. Angiopoietin-1 and tyrosine kinase signaling are essential for regulating blood vessel development and the stability of mature vessels. The expression of Angiopoietin-2 in the absence of vascular endothelial growth factor (VEGF) leads to endothelial cell death and vascular regression. Increased levels of Ang2 promote tumor angiogenesis,
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, ...
, and inflammation. Effective means to control Ang2 in inflammation and cancer should have clinical value. Angiopoeitin, more specifically Ang-1 and Ang-2, work hand in hand with VEGF to mediate angiogenesis. Ang-2 works as an antagonist of Ang-1 and promotes vessel regression if VEGF is not present. Ang-2 works with VEGF to facilitate cell proliferation and migration of endothelial cells. Changes in expression of Ang-1, Ang-2 and VEGF have been reported in the rat brain after cerebral ischemia.


Angiogenesis signaling

To migrate, the endothelial cells need to loosen the endothelial connections by breaking down the
basal lamina The basal lamina is a layer of extracellular matrix secreted by the epithelial cells, on which the epithelium sits. It is often incorrectly referred to as the basement membrane, though it does constitute a portion of the basement membrane. The ba ...
and the ECM scaffold of blood vessels. These connections are a key determinant of vascular permeability and relieve peri-endothelial cell contact, which is also a major factor in vessel stability and maturity. After the physical barrier is removed, under the influence of the growth factors VEGF with addition contributions of other factors like angiopoietin-1, integrins, and
chemokines Chemokines (), or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition ...
play an essential role. VEGF and ang-1 are involved in endothelial tube formation.


Vascular permeability signaling

Angiopoietin-1 and angiopoietin-2 are modulators of endothelial permeability and barrier function. Endothelial cells secrete angiopoietin-2 for
autocrine signaling Autocrine signaling is a form of cell signaling in which a cell secretes a hormone or chemical messenger (called the autocrine agent) that binds to autocrine receptors on that same cell, leading to changes in the cell. This can be contrasted with pa ...
while
parenchymal Parenchyma () is the bulk of functional substance in an animal organ or structure such as a tumour. In zoology it is the name for the tissue that fills the interior of flatworms. Etymology The term ''parenchyma'' is New Latin from the word ...
cells of the extravascular tissue secrete angiopoietin-2 onto endothelial cells for
paracrine signaling Paracrine signaling is a form of cell signaling, a type of cellular communication in which a cell produces a signal to induce changes in nearby cells, altering the behaviour of those cells. Signaling molecules known as paracrine factors diffuse ove ...
, which then binds to the extracellular matrix and is stored within the endothelial cells.


Cancer

Angiopoietin-2 has been proposed as a biomarker in different cancer types. Angiopoietin-2 expression levels are proportional to the cancer stage for both small and non-small cell lung cancers. It has been also implicated to play role in hepatocellular and endometrial carcinoma-induced angiogenesis. Experiments using blocking antibodies for angiopoietin-2 have shown to decrease metastasis to lungs and lymph nodes.


Clinical relevance

Deregulation of angiopoietin and the tyrosine kinase pathway is common in blood-related diseases such as
diabetes Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ap ...
,
malaria Malaria is a mosquito-borne infectious disease that affects humans and other animals. Malaria causes symptoms that typically include fever, tiredness, vomiting, and headaches. In severe cases, it can cause jaundice, seizures, coma, or death. S ...
,
sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
, and pulmonary hypertension. This is demonstrated by an increased ratio of angiopoietin-2 and angiopoietin-1 in blood serum. To be specific, angiopoietin levels provide an indication for
sepsis Sepsis, formerly known as septicemia (septicaemia in British English) or blood poisoning, is a life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage is follo ...
. Research on angiopoietin-2 has shown that it is involved in the onset of septic shock. The combination of fever and high levels of angiopoietin-2 are correlated with a greater prospect of the development of septic shock. It has also been shown that imbalances between angiopoietin-1 and angiopoietin-2 signaling can act independently of each other. One angiopoietin factor can signal at high levels while the other angiopoieting factor remains at baseline level signaling. Angiopoietin-2 is produced and stored in Weibel-Palade bodies in endothelial cells and acts as a
TEK tyrosine kinase Angiopoietin-1 receptor also known as CD202B (cluster of differentiation 202B) is a protein that in humans is encoded by the ''TEK'' gene. Also known as TIE2, it is an angiopoietin receptor. Function The TEK receptor tyrosine kinase is expres ...
antagonist. As a result, the promotion of endothelial activation, destabilization, and inflammation are promoted. Its role during angiogenesis depends on the presence of Vegf-a. Serum levels of angiopoietin-2 expression are associated with the growth of
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
, angiogenesis, and overall survival in oral
squamous cell carcinoma Squamous-cell carcinomas (SCCs), also known as epidermoid carcinomas, comprise a number of different types of cancer that begin in squamous cells. These cells form on the surface of the skin, on the lining of hollow organs in the body, and on the ...
. Circulating angiopoietin-2 is a marker for early
cardiovascular 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, h ...
in children on chronic dialysis. Kaposi’s sarcoma-associated herpesvirus induces rapid release of angiopoietin-2 from endothelial cells. Angiopoietin-2 is elevated in patients with
angiosarcoma Angiosarcoma is a rare and aggressive cancer that starts in the endothelial cells that line the walls of blood vessels or lymphatic vessels. Since they are made from vascular lining, they can appear anywhere and at any age, but older people are ...
. Research has shown angiopoietin signaling to be relevant in treating cancer as well. During tumor growth, pro-angiogenic molecules and anti-angiogenic molecules are off balance. Equilibrium is disrupted such that the number of pro-angiogenic molecules are increased. Angiopoietins have been known to be recruited as well as VEGFs and platelet-derived growth factors (
PDGF 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 ...
s). This is relevant for clinical use relative to cancer treatments because the inhibition of angiogenesis can aid in suppressing tumor proliferation.


References


External links

* * {{Growth factor receptor modulators Angiology Growth factors