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 mainly by processes of sprouting and ...

. 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 produced by a broad range of cells, including immune cells like macrophages, B cell, B lymphocytes, T cell, T lymphocytes ...

are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling

smooth muscle cells Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal muscle, skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non-striated ...

surrounding vessels. There are now four identified angiopoietins: ANGPT1,

ANGPT2 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 Angiopoietin#Cl ...

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 predominant ...

, ANGPT4. In addition, there are a number of proteins that are closely related to ('like') angiopoietins ( Angiopoietin-related protein 1, , , , , , , ). 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, 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 amin ...

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, carboxy 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 t ...

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. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...

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,

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 and Tie-2. The two receptor pathways are named as a result of their role in mediating cell signals by inducing the

phosphorylation In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writ ...

of specific tyrosines. This in turn initiates the binding and activation of downstream intracellular

enzymes An enzyme () is a protein that acts as a biological catalyst 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 pro ...

, a process known as cell signaling.

Tie-2

Tie-2/Ang-1 signaling activates β1-

integrin Integrins are transmembrane receptors that help 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, o ...

and N-

cadherin Cadherins (named for "calcium-dependent adhesion") are cell adhesion molecules important in forming adherens junctions that let cells adhere to each other. Cadherins are a class of type-1 transmembrane proteins, and they depend on calcium (Ca2+) ...

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 first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within the ...

(HSC) interactions with

extracellular matrix In biology, the extracellular matrix (ECM), also called intercellular matrix (ICM), is a network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide structural and bio ...

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 (: 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 malnutr ...

, Tie-2/Ang-1 signaling is predominantly expressed by osteoblastic 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 with a 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 ...

for Tie-2 receptors. Tie-1 heterodimerizes with Tie-2 to enhance and modulate signal transduction of Tie-2 for vascular development and maturation. These Tyrosine kinase receptors are typically expressed on vascular endothelial cells and specific

macrophages Macrophages (; abbreviated MPhi, φ, MΦ or MP) are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris and foreign substances, which do not have proteins that ...

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 (sugar) 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 a ...

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 spreading 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, ...

, 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 b ...

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 addit ...

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 ...

while

parenchymal upright=1.6, Lung parenchyma showing damage due to large subpleural bullae. Parenchyma () is the bulk of functional substance in an animal organ such as the brain or lungs, or a structure such as a tumour. In zoology, it is the tissue that ...

cells of the extravascular tissue secrete angiopoietin-2 onto endothelial cells for

paracrine signaling In cellular biology, 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 parac ...

, which then binds to the extracellular matrix and is stored within the endothelial cells. Wikipedia Ang-1 structure

Angiopoietin-1 and the Tie2

Angiopoietin-1 has been classified as a Tie2 agonist. Due to Angiopoietin-2 being an antagonist researchers looked into functional differences between Ang-1 and Ang-2 to learn more about the Tie2 signaling initiation. Early structural analysis revealed that their differences were concentrated in the P-domain of the fibrinogen. Studies showed that the P-domain consisted of non-polar residues. Providing stability for the Calcium Ion and the Tie2 complex. Studies showed that three residues in the P-domain where responsible for the agonist behavior of Ang-1: Leu, His, Asp. This was significant because this knowledge could be applied to Ang-2 studies. Through the substitution of these residues the signaling of Ang-2 could be inhibited. Making it valuable for cancer drug discovery.

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 mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...

malaria Malaria is a Mosquito-borne disease, mosquito-borne infectious disease that affects vertebrates and ''Anopheles'' mosquitoes. Human malaria causes Signs and symptoms, symptoms that typically include fever, Fatigue (medical), fatigue, vomitin ...

sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...

, and

pulmonary hypertension Pulmonary hypertension (PH or PHTN) is a condition of increased blood pressure in the pulmonary artery, arteries of the lungs. Symptoms include dypsnea, shortness of breath, Syncope (medicine), fainting, tiredness, chest pain, pedal edema, swell ...

. 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

. 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 expr ...

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 antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...

, angiogenesis, and overall survival in oral

squamous cell carcinoma Squamous-cell carcinoma (SCC), also known as epidermoid carcinoma, comprises 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 any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...

in children on chronic dialysis.

Kaposi's sarcoma-associated herpesvirus Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus. It is also called Human herpesvirus 8, or HHV-8 in short. This virus causes Kaposi's sarcoma, a cancer commonly occurring in AIDS patients, as well as primary ...

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 Endothelium, vascular lining, they can appear anywhere and at any age, but older ...

. 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 ...

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 Angiogenesis Growth factors