Pericyte
Encyclopedia
A pericyte is a type of cell found in the central nervous system
. These cells play an integral role in the maintenance of the blood brain barrier as well as several other homeostatic
and hemostatic
functions of the brain
. Pericytes are also a key component of the neurovascular unit, which also includes endothelial cells, astrocytes, and neurons. Pericytes provide a variety of functions such as capillary
blood flow regulation, clearance and phagocytosis of cellular debris, and regulating blood brain barrier permeability. Pericytes can also work to stabilize and monitor the maturation of endothelial cells by direct communication between the cell membrane and paracrine signaling. It has also been revealed in recent studies that a lack of pericytes in the central nervous system can cause a breakdown of the blood brain barrier and lead to other degenerative changes in the brain.
of the pericyte compared to the flat elongated nucleus of the endothelial cells. Pericytes also project finger-like extensions that wrap around the capillary wall. Both pericytes and endothelial cells share a basement membrane
where a variety of intercellular connections are made. Many types of integrin
molecules facilitate communication between pericytes and endothelial cells separated by the basement membrane. Pericytes can also form direct connections with neighboring cells by forming peg and socket arrangements in which parts of the cells interlock. At these interlocking sites, gap junctions can be formed which allow the pericytes and neighboring cells to exchange ions and other small molecules. Important molecules in these intercellular connections include N-cadherin, fibronectin
, and various integrins.
Aside from blood brain barrier formation, pericytes also play an active role in its functionality by controlling the flow within blood vessels and between blood vessels and the brain. They are contractile cells so they can open or close a given amount to allow (or disallow) certain sized particles to flow through the vessel. Such regulation of blood flow is beneficial to neuronal function because it protects the brain from undesired particles. Without the presence of pericytes, a process known as transcytosis may occur within the blood brain barrier. This essentially means that there is little to no regulation by the barrier and particles of varying sizes, including large plasma proteins, can easily enter the brain . This passage of particles can be adverse to the brain because many of these particles can be toxic. Thus, pericytes play a critical role in assuring that harmful chemicals do not enter the brain and disrupt neurological function. Pericyte functionality (or disfunctionality) is also theorized to contribute to neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS. Furthermore, the elasticity of pericyte is beneficial because they can expand to reduce inflammation and allow harmful substances to diffuse out of the brain .
These cells also play a key role in increasing microcirculation and reducing the effects or brain aging. In a study involving adult pericyte-deficient mice, the absence of pericytes in the brain has been found to lead to vascular damage from loss of microcirculation and cerebral blood flow. Such blood flow is imperative to mediate the effects caused by stress, hypoxia and several other conditions which may alter homeostasis. In addition, when pericytes are not present, the blood brain barrier does not degrade certain neurotoxic and vasculotoxic serum proteins which thus bolsters degenerative changes. Such changes include inflammation as well as learning and memory impairment .
It is also important to note that pericytes maintain plasticity and thus can differentiate into various other cell types including, smooth muscle cell as well as fibroblasts and other mesenchymal cells. Such versatility is conducive because they actively remodel blood vessels throughout the body and must be homogenous with the surroundings. .
Aside from creating and remodeling blood vessels in a viable fashion, pericytes have been found to protect endothelial cells from death via apoptosis or cytotoxic elements. It has been studied in vivo that pericytes release a hormone known as pericytic aminopeptidase N/pAPN that may help to promote angiogenesis. When this hormone was mixed with cerebral endothelial cells and astrocytes, the pericytes grouped into structures that resembled capillaries. Furthermore, if experimental group contained all of the following with the exception of pericytes, the endothelial cells would undergo apoptosis. That being said, it was concluded that pericytes must be present to assure the proper function of endothelial cells and astrocytes must be present to assure that both remain in contact. If not, than proper angiogenesis cannot occur . In addition, it has been found that pericytes contribute to the survival of endothelial cells because they secrete the protein Bcl-w during cellular crosstalk. Bcl-w is an instrumental protein in the pathway that enforces VEGF-A expression discourages apoptosis. That being said, pericytes also promotes protection of endothelial cells against several cytotoxic elements
is a rare vascular neoplasm, or abnormal growth, that may either be benign or malignant. In its malignant form, metastasis to the lungs, liver, brain, and extremities may occur. It most commonly manifests itself in the femur and proximal tibia as a bone sarcoma, and is usually found in older individuals, though cases have been found in children. Hemangiopericytoma is caused by the excessive layering of sheets of pericytes around improperly formed blood vessels. Diagnosis of this tumor is difficult because of the inability to distinguish pericytes from other types of cells using light microscopy. Treatment may involve surgical removal and radiation therapy, depending on the level of bone penetration and stage in the tumor's development.
. Studies have found that pericytes are essential in diabetic individuals to protect the endothelial cells of retinal capillaries. With the loss of perictyes, microaneuryisms form in the capillaries. In response, the retina either increases its vascular permeability, leading to swelling of the eye through a macular edema
, or forms new vessels that permeate into the vitreous membrane
of the eye. The end result is reduction or loss of vision. While it is unclear why pericytes are lost in diabetic patients, one hypothesis is that toxic sorbitol
and advanced glycation end products accumulate in the pericytes.
and Multiple Sclerosis
.
There are several pathways of communication between the endothelial cells and mural cells
. The first is transforming growth factor
signaling, which is mediated by endothelial cells. This is important for pericyte differentiation. Angiopoietin 1
and Tie-2 signaling is essential for maturation and stabilization of endothelial cells. Platelet-derived growth factor
pathway signaling from endothelial cells recruit pericytes, so that pericytes can migrate to growing vessels. If this pathway is blocked, it leads to pericyte deficiency. Sphingosine-1-phosphate
(S1P) signaling also aides in pericyte recruitment by communication through G protein-coupled receptors. S1P signals through GTPases that promote N-cadherin trafficking to endothelial membranes. This trafficking strengthens contacts with pericytes.
Communication between endothelial cells and pericytes are important. Inhibiting the PDGF pathway leads to pericyte deficiency. This causes endothelial hyperplasia
, abnormal junctions, and diabetic retinotropy. A lack of pericytes also causes an upregulation of vascular endothelial growth factor
(VEGF), leading to vascular leakage and hemorrhage. Also, angiopoietin 2 can act as an antagonist to Tie-2. This destabilizes the endothelial cells, which accounts for less endothelial cell and pericyte interaction. This can actually lead to the formation of tumors. Similar to the inhibition of the PDGF pathway, angiopoietin 2 reduces levels of pericyte, leading to diabetic retinopathy.
, scarring occurs to preserve the integrity of surrounding cells. Usually, astrocytes are associated with the scarring and are called glial scars
. However, there is a stromal or nonglial component of the scarring, and there is evidence that perivascular pericytes play a critical role in assisting scar formation.
An experiment was conducted on mice that have been genetically labeled using glutamate aspartate transporter
(Glast). They found two different subtypes of pericytes and termed them subtype A and B. Subtype A accounts for about 10% of the pericytes in the adult spinal cord and plays a critical role in scarring. Subtype B accounts for the rest of the pericytes and has desmin
and alpha smooth muscles. After the two subtypes were isolated and labeled, an incision was made to the dorsal part of the brain. Typically in an uninjured spinal cord there are ten times as many astrocytes than subtype A pericytes. However, two weeks after the injury, the number of pericytes were double that of the astrocytes. Subtype A were three times more prevalent than subtype B. The main difference in prevalence arises from the fact that subtype A is able to detach from blood vessel walls and can send tiny projections to nearby cells and deposit extracellular matrix proteins.
The scarring is highly compartmentalized. The pericytes form the core of the scar, while ependymal cells form a second layer around the core, followed by another layer of astrocytes that originated through self-duplication.
Inhibition of subtype A pericyte generation caused improper closing of spinal cord incisions, which supports the idea that pericytes are important for scarring.
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. These cells play an integral role in the maintenance of the blood brain barrier as well as several other homeostatic
Homeostasis
Homeostasis is the property of a system that regulates its internal environment and tends to maintain a stable, constant condition of properties like temperature or pH...
and hemostatic
Hemostasis
Hemostasis or haemostasis is a process which causes bleeding to stop, meaning to keep blood within a damaged blood vessel . Most of the time this includes blood changing from a liquid to a solid state. Intact blood vessels are central to moderating blood's tendency to clot...
functions of the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. Pericytes are also a key component of the neurovascular unit, which also includes endothelial cells, astrocytes, and neurons. Pericytes provide a variety of functions such as capillary
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...
blood flow regulation, clearance and phagocytosis of cellular debris, and regulating blood brain barrier permeability. Pericytes can also work to stabilize and monitor the maturation of endothelial cells by direct communication between the cell membrane and paracrine signaling. It has also been revealed in recent studies that a lack of pericytes in the central nervous system can cause a breakdown of the blood brain barrier and lead to other degenerative changes in the brain.
Morphology
In the central nervous system, pericytes wrap around the endothelial cells that line the outside of the capillary. These two types of cells can be easily distinguished from one another based on the presence of the prominent round nucleusCell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
of the pericyte compared to the flat elongated nucleus of the endothelial cells. Pericytes also project finger-like extensions that wrap around the capillary wall. Both pericytes and endothelial cells share a basement membrane
Basement membrane
The basement membrane is a thin sheet of fibers that underlies the epithelium, which lines the cavities and surfaces of organs including skin, or the endothelium, which lines the interior surface of blood vessels.- Composition :...
where a variety of intercellular connections are made. Many types of integrin
Integrin
Integrins are receptors that mediate attachment between a cell and the tissues surrounding it, which may be other cells or the ECM. They also play a role in cell signaling and thereby regulate cellular shape, motility, and the cell cycle....
molecules facilitate communication between pericytes and endothelial cells separated by the basement membrane. Pericytes can also form direct connections with neighboring cells by forming peg and socket arrangements in which parts of the cells interlock. At these interlocking sites, gap junctions can be formed which allow the pericytes and neighboring cells to exchange ions and other small molecules. Important molecules in these intercellular connections include N-cadherin, fibronectin
Fibronectin
Fibronectin is a high-molecular weight glycoprotein of the extracellular matrix that binds to membrane-spanning receptor proteins called integrins. In addition to integrins, fibronectin also binds extracellular matrix components such as collagen, fibrin and heparan sulfate proteoglycans...
, and various integrins.
Blood Brain Barrier
Pericytes play a crucial role in the formation and functionality of the selective permeable space between the circulatory and central nervous system that is the blood brain barrier. This barrier is composed of endothelial cells and assures the protection and functionality of the brain and central nervous system. Although it had be theorized that astrocytes were largely important in the postnatal formation of this barrier, it has been found that pericytes are now largely responsible for this role. Pericytes are responsible for tight junction formation and vesicle trafficking amongst endothelial cells. Furthermore, they allow the formation of the blood brain barrier by inhibiting the effects of CNS immune cells (which can damage the formation of the barrier) and by reducing the expression of molecules that increase vascular permeability .Aside from blood brain barrier formation, pericytes also play an active role in its functionality by controlling the flow within blood vessels and between blood vessels and the brain. They are contractile cells so they can open or close a given amount to allow (or disallow) certain sized particles to flow through the vessel. Such regulation of blood flow is beneficial to neuronal function because it protects the brain from undesired particles. Without the presence of pericytes, a process known as transcytosis may occur within the blood brain barrier. This essentially means that there is little to no regulation by the barrier and particles of varying sizes, including large plasma proteins, can easily enter the brain . This passage of particles can be adverse to the brain because many of these particles can be toxic. Thus, pericytes play a critical role in assuring that harmful chemicals do not enter the brain and disrupt neurological function. Pericyte functionality (or disfunctionality) is also theorized to contribute to neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS. Furthermore, the elasticity of pericyte is beneficial because they can expand to reduce inflammation and allow harmful substances to diffuse out of the brain .
These cells also play a key role in increasing microcirculation and reducing the effects or brain aging. In a study involving adult pericyte-deficient mice, the absence of pericytes in the brain has been found to lead to vascular damage from loss of microcirculation and cerebral blood flow. Such blood flow is imperative to mediate the effects caused by stress, hypoxia and several other conditions which may alter homeostasis. In addition, when pericytes are not present, the blood brain barrier does not degrade certain neurotoxic and vasculotoxic serum proteins which thus bolsters degenerative changes. Such changes include inflammation as well as learning and memory impairment .
Angiogenesis and the Survival of Endothelial Cells
Pericytes are also associated with the allowing Endothelial Cells to differentiate, multiply, form vascular branches, survive apoptotic symbols and travel throughout the body. Certain pericytes, known as microvascular pericytes develop around the walls of capillaries and help to serve this function. Microvascular pericytes may not be contractile cells because they lack a-actin isoforms; structures that are common amongst other contractile cells. These cells communicate with endothelial cells via gap junctions and in turn cause endothelial cells to proliferate or be selectively inhibited. If this process did not occur, hyperplasia and abnormal vascular morphogenesis could occur. These types of pericytes can also phagocytose exogenous proteins. This suggests that the cell type might have been derived from microglia. .It is also important to note that pericytes maintain plasticity and thus can differentiate into various other cell types including, smooth muscle cell as well as fibroblasts and other mesenchymal cells. Such versatility is conducive because they actively remodel blood vessels throughout the body and must be homogenous with the surroundings. .
Aside from creating and remodeling blood vessels in a viable fashion, pericytes have been found to protect endothelial cells from death via apoptosis or cytotoxic elements. It has been studied in vivo that pericytes release a hormone known as pericytic aminopeptidase N/pAPN that may help to promote angiogenesis. When this hormone was mixed with cerebral endothelial cells and astrocytes, the pericytes grouped into structures that resembled capillaries. Furthermore, if experimental group contained all of the following with the exception of pericytes, the endothelial cells would undergo apoptosis. That being said, it was concluded that pericytes must be present to assure the proper function of endothelial cells and astrocytes must be present to assure that both remain in contact. If not, than proper angiogenesis cannot occur . In addition, it has been found that pericytes contribute to the survival of endothelial cells because they secrete the protein Bcl-w during cellular crosstalk. Bcl-w is an instrumental protein in the pathway that enforces VEGF-A expression discourages apoptosis. That being said, pericytes also promotes protection of endothelial cells against several cytotoxic elements
Pathologies
Because of their crucial role in maintaining and regulating endothelial cell structure and blood flow, abnormalities in pericyte function are seen in many pathologies. They may either be present in excess, leading to diseases such as hypertension and tumor formation, or in deficiency, leading to neurodegenerative diseases.Hemangiopericytoma
HemangiopericytomaHemangiopericytoma
A hemangeopericytoma is a type of soft tissue sarcoma that originates in the pericytes in the walls of capillaries. When inside the nervous system, although not strictly a meningioma tumor, it is a meningeal tumor with an especially aggressive behavior.It was characterized in...
is a rare vascular neoplasm, or abnormal growth, that may either be benign or malignant. In its malignant form, metastasis to the lungs, liver, brain, and extremities may occur. It most commonly manifests itself in the femur and proximal tibia as a bone sarcoma, and is usually found in older individuals, though cases have been found in children. Hemangiopericytoma is caused by the excessive layering of sheets of pericytes around improperly formed blood vessels. Diagnosis of this tumor is difficult because of the inability to distinguish pericytes from other types of cells using light microscopy. Treatment may involve surgical removal and radiation therapy, depending on the level of bone penetration and stage in the tumor's development.
Diabetic retinopathy
The retina of diabetic individuals often exhibits loss of perictyes, and this loss is a characteristic factor of the early stages of diabetic retinopathyDiabetic retinopathy
Diabetic retinopathy is retinopathy caused by complications of diabetes mellitus, which can eventually lead to blindness....
. Studies have found that pericytes are essential in diabetic individuals to protect the endothelial cells of retinal capillaries. With the loss of perictyes, microaneuryisms form in the capillaries. In response, the retina either increases its vascular permeability, leading to swelling of the eye through a macular edema
Macular edema
Macular edema occurs when fluid and protein deposits collect on or under the macula of the eye and causes it to thicken and swell. The swelling may distort a person's central vision, as the macula is near the center of the retina at the back of the eyeball...
, or forms new vessels that permeate into the vitreous membrane
Vitreous membrane
The vitreous membrane is a layer of collagen separating the vitreous humour from the rest of the eye. At least two parts have been identified anatomically. The posterior hyaloid membrane separates the rear of the vitreous from the retinaThe anterior hyaloid membrane separates the front of the...
of the eye. The end result is reduction or loss of vision. While it is unclear why pericytes are lost in diabetic patients, one hypothesis is that toxic sorbitol
Sorbitol
Sorbitol, also known as glucitol, Sorbogem® and Sorbo®, is a sugar alcohol that the human body metabolizes slowly. It can be obtained by reduction of glucose, changing the aldehyde group to a hydroxyl group. Sorbitol is found in apples, pears, peaches, and prunes...
and advanced glycation end products accumulate in the pericytes.
Neurodegenerative Diseases
Studies have found that pericyte loss in the adult and aging brain leads to the disruption of proper cerebral perfusion and maintenance of the blood-brain barrier, which causes neurodegeneration and neuroinflammation. The apoptosis of pericytes in the aging brain may be the result of a failure in communication between growth factors and receptors on pericytes. Platelet-derived growth factor B (PDGF-B)is released from endothelial cells in brain vasculature and binds to the receptor PDGFR-Beta on pericytes, initiating their proliferation and migration for proper vasculature maintenance. When this signalling is disrupted, pericytes undergo apoptosis, leading to many neurodegenerative diseases including Alzheimer's diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and Multiple Sclerosis
Multiple sclerosis
Multiple sclerosis is an inflammatory disease in which the fatty myelin sheaths around the axons of the brain and spinal cord are damaged, leading to demyelination and scarring as well as a broad spectrum of signs and symptoms...
.
Research
Researchers have taken pericytes from the pancreas and then reinjected them into an injured muscle. The cells immediately began regenerating muscle tissue.Endothelial and Pericyte Interactions
Endothelial cell and pericytes are interdependent, so failure of proper communication between the two cells can lead to numerous human pathologies.There are several pathways of communication between the endothelial cells and mural cells
Mural cells
The term mural cell refers generally to vascular smooth muscle cells and pericytes, both involved in the formation of normal vasculature and responsive to vascular endothelial growth factor . The weakness and disorganization of tumor vasculature is partly due to the inability of tumors to recruit...
. The first is transforming growth factor
Transforming growth factor
Transforming growth factor is used to describe two classes of polypeptide growth factors, TGFα and TGFβ....
signaling, which is mediated by endothelial cells. This is important for pericyte differentiation. Angiopoietin 1
Angiopoietin 1
Angiopoietin 1 is a type of angiopoietin and is encoded by the gene ANGPT1.-Interactions:Angiopoietin 1 has been shown to interact with TEK tyrosine kinase.-Further reading:...
and Tie-2 signaling is essential for maturation and stabilization of endothelial cells. Platelet-derived growth factor
Platelet-derived growth factor
In molecular biology, platelet-derived growth factor is one of the numerous growth factors, or proteins that regulate cell growth and division. In particular, it plays a significant role in blood vessel formation , the growth of blood vessels from already-existing blood vessel tissue. Uncontrolled...
pathway signaling from endothelial cells recruit pericytes, so that pericytes can migrate to growing vessels. If this pathway is blocked, it leads to pericyte deficiency. Sphingosine-1-phosphate
Sphingosine-1-phosphate
Sphingosine-1-phosphate is a signaling sphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcohol, which is sphingosine.-Production:...
(S1P) signaling also aides in pericyte recruitment by communication through G protein-coupled receptors. S1P signals through GTPases that promote N-cadherin trafficking to endothelial membranes. This trafficking strengthens contacts with pericytes.
Communication between endothelial cells and pericytes are important. Inhibiting the PDGF pathway leads to pericyte deficiency. This causes endothelial hyperplasia
Hyperplasia
Hyperplasia means increase in number of cells/proliferation of cells. It may result in the gross enlargement of an organ and the term is sometimes mixed with benign neoplasia/ benign tumor....
, abnormal junctions, and diabetic retinotropy. A lack of pericytes also causes an upregulation of vascular endothelial growth factor
Vascular endothelial growth factor
Vascular endothelial growth factor is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate....
(VEGF), leading to vascular leakage and hemorrhage. Also, angiopoietin 2 can act as an antagonist to Tie-2. This destabilizes the endothelial cells, which accounts for less endothelial cell and pericyte interaction. This can actually lead to the formation of tumors. Similar to the inhibition of the PDGF pathway, angiopoietin 2 reduces levels of pericyte, leading to diabetic retinopathy.
Scarring
After an injury in the CNSCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
, scarring occurs to preserve the integrity of surrounding cells. Usually, astrocytes are associated with the scarring and are called glial scars
Glial scar
Glial scar formation is a reactive cellular process involving astrogliosis that occurs after injury to the Central Nervous System. As with scarring in other organs and tissues, the glial scar is the body's mechanism to protect and begin the healing process in the nervous system...
. However, there is a stromal or nonglial component of the scarring, and there is evidence that perivascular pericytes play a critical role in assisting scar formation.
An experiment was conducted on mice that have been genetically labeled using glutamate aspartate transporter
Glutamate aspartate transporter
Solute carrier family 1 , member 3, also known as SLC1A3,is a protein that, in humans, is encoded by the SLC1A3 gene...
(Glast). They found two different subtypes of pericytes and termed them subtype A and B. Subtype A accounts for about 10% of the pericytes in the adult spinal cord and plays a critical role in scarring. Subtype B accounts for the rest of the pericytes and has desmin
Desmin
Desmin is a protein that in humans is encoded by the DES gene.Desmin is a type III intermediate filament found near the Z line in sarcomeres. It was first described in 1976, first purified in 1977, the gene was cloned in 1989, and the first knock-out mouse was created in 1996. Desmin is only...
and alpha smooth muscles. After the two subtypes were isolated and labeled, an incision was made to the dorsal part of the brain. Typically in an uninjured spinal cord there are ten times as many astrocytes than subtype A pericytes. However, two weeks after the injury, the number of pericytes were double that of the astrocytes. Subtype A were three times more prevalent than subtype B. The main difference in prevalence arises from the fact that subtype A is able to detach from blood vessel walls and can send tiny projections to nearby cells and deposit extracellular matrix proteins.
The scarring is highly compartmentalized. The pericytes form the core of the scar, while ependymal cells form a second layer around the core, followed by another layer of astrocytes that originated through self-duplication.
Inhibition of subtype A pericyte generation caused improper closing of spinal cord incisions, which supports the idea that pericytes are important for scarring.
See also
- HemangiopericytomaHemangiopericytomaA hemangeopericytoma is a type of soft tissue sarcoma that originates in the pericytes in the walls of capillaries. When inside the nervous system, although not strictly a meningioma tumor, it is a meningeal tumor with an especially aggressive behavior.It was characterized in...
- Mural cell
- MesoangioblastMesoangioblastA mesoangioblast is a mesenchymal-like cell, associated with the walls of the large vessels. Mesoangioblasts exhibit many similarities to pericytes found in the small vessels. Mesoangioblasts are relatively undifferentiated cells with the potential to progress down the endothelial or mesodermal...
- Diabetic retinopathy caused by death of pericytes
