Pericyte

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Pericyte
Microvessel.jpg
Transmission electron micrograph of a microvessel displaying pericytes that are lining the outer surface of endothelial cells that are encircling an erythrocyte (E).
Details
Identifiers
Latin pericytus
MeSH D020286
TH H3.09.02.0.02006
FMA 63174
Anatomical terms of microanatomy

Pericytes (formerly called Rouget cells) [1] are multi-functional mural cells of the microcirculation that wrap around the endothelial cells that line the capillaries throughout the body. [2] Pericytes are embedded in the basement membrane of blood capillaries, where they communicate with endothelial cells by means of both direct physical contact and paracrine signaling. [3] The morphology, distribution, density and molecular fingerprints of pericytes vary between organs and vascular beds. [4] [5] Pericytes help in the maintainenance of homeostatic and hemostatic functions in the brain, where one of the organs is characterized with a higher pericyte coverage, and also sustain the blood–brain barrier. [6] These cells are also a key component of the neurovascular unit, which includes endothelial cells, astrocytes, and neurons. [7] [8] Pericytes have been postulated to regulate capillary blood flow [9] [10] [11] [12] and the clearance and phagocytosis of cellular debris in vitro. [13] Pericytes stabilize and monitor the maturation of endothelial cells by means of direct communication between the cell membrane as well as through paracrine signaling. [14] A deficiency of pericytes in the central nervous system can cause increased permeability of the blood–brain barrier. [6]

Contents

Structure

Gap cell junction created between two neighboring cells by connexin. Gap cell junction-en.svg
Gap cell junction created between two neighboring cells by connexin.

In the central nervous system (CNS), pericytes wrap around the endothelial cells that line the inside of the capillary. These two types of cells can be easily distinguished from one another based on the presence of the prominent round nucleus of the pericyte compared to the flat elongated nucleus of the endothelial cells. [7] Pericytes also project finger-like extensions that wrap around the capillary wall, allowing the cells to regulate capillary blood flow. [6]

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. [6] Pericytes can also form direct connections with neighboring cells by forming peg and socket arrangements in which parts of the cells interlock, similar to the gears of a clock. At these interlocking sites, gap junctions can be formed, which allow the pericytes and neighboring cells to exchange ions and other small molecules. [6] Important molecules in these intercellular connections include N-cadherin, fibronectin, connexin and various integrins. [7]

In some regions of the basement membrane, adhesion plaques composed of fibronectin can be found. These plaques facilitate the connection of the basement membrane to the cytoskeletal structure composed of actin, and the plasma membrane of the pericytes and endothelial cells. [6]

Function

Skeletal muscle regeneration and fat formation

Pericytes in the skeletal striated muscle are of two distinct populations, each with its own role. The first pericyte subtype (Type-1) can differentiate into fat cells while the other (Type-2) into muscle cells. Type-1 characterized by negative expression for nestin (PDGFRβ+CD146+Nes-) and type-2 characterized by positive expression for nestin (PDGFRβ+CD146+Nes+). While both types are able to proliferate in response to glycerol or BaCl2-induced injury, type-1 pericytes give rise to adipogenic cells only in response to glycerol injection and type-2 become myogenic in response to both types of injury. The extent to which type-1 pericytes participate in fat accumulation is not known.

Angiogenesis and the survival of endothelial cells

Pericytes are also associated with endothelial cell differentiation and multiplication, angiogenesis, survival of apoptotic signals and travel. 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, as they lack alpha-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 result. These types of pericyte can also phagocytose exogenous proteins. This suggests that the cell type might have been derived from microglia. [15]

A lineage relationship to other cell types has been proposed, including smooth muscle cells, [16] neural cells, [16] NG2 glia, [17] muscle fibers, adipocytes, as well as fibroblasts [18] and other mesenchymal stem cells. However, whether these cells differentiate into each other is an outstanding question in the field. Pericytes' regenerative capacity is affected by aging. [18] Such versatility is useful, as they actively remodel blood vessels throughout the body and can thereby blend homogeneously with the local tissue environment. [19]

Aside from creating and remodeling blood vessels, pericytes have been found to protect endothelial cells from death via apoptosis or cytotoxic elements. It has been shown 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 as well as astrocytes, the pericytes grouped into structures that resembled capillaries. Furthermore, when the experimental group contained all of the following with the exception of pericytes, the endothelial cells would undergo apoptosis. [ further explanation needed ] It was thus concluded that pericytes must be present to ensure the proper function of endothelial cells, and astrocytes must be present to ensure that both remain in contact. If not, then proper angiogenesis cannot occur. [20] It has also been found that pericytes contribute to the survival of endothelial cells, as they secrete the protein Bcl-w during cellular crosstalk. Bcl-w is an instrumental protein in the pathway that enforces VEGF-A expression and discourages apoptosis. [21] Although there is some speculation as to why VEGF is directly responsible for preventing apoptosis, it is believed to be responsible for modulating apoptotic signal transduction pathways and inhibiting activation of apoptosis-inducing enzymes. Two biochemical mechanisms utilized by VEGF to accomplish this would be phosphorylation of extracellular regulatory kinase 1 (ERK-1, also known as MAPK3), which sustains cell survival over time, and inhibition of stress-activated protein kinase/c-jun-NH2 kinase, which also promotes apoptosis. [22]

Blood–brain barrier

Pericytes play a crucial role in the formation and functionality of the blood–brain barrier. This barrier is composed of endothelial cells and ensures the protection and functionality of the brain and central nervous system. It has been found that pericytes are crucial to the postnatal formation of this barrier. 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. [23]

Aside from blood–brain barrier formation, pericytes also play an active role in its functionality. Animal models of developmental loss of pericytes show increased endothelial transcytosis, as well as skewed arterio-venous zonation, increased expression of leukocyte adhesion molecules and microaneurysms. [24] [25] Loss or dysfunction of pericytes is also theorized to contribute to neurodegenerative diseases such as Alzheimer's, [26] [27] [28] Parkinson's and ALS [29] through breakdown of the blood-brain barrier.

Blood flow

Increasing evidence suggests that pericytes can regulate blood flow at the capillary level. For the retina, movies have been published [12] showing that pericytes constrict capillaries when their membrane potential is altered to cause calcium influx, and in the brain it has been reported that neuronal activity increases local blood flow by inducing pericytes to dilate capillaries before upstream arteriole dilation occurs. [11] This area is controversial, with a 2015 study claiming that pericytes do not express contractile proteins and are not capable of contraction in vivo, [10] although the latter paper has been criticised for using a highly unconventional definition of pericyte which explicitly excludes contractile pericytes. [30] It appears that different signaling pathways regulate the constriction of capillaries by pericytes and of arterioles by smooth muscle cells. [31] Recent studies on rats have found such a signaling pathway in which after spinal cord injury and induced hypoxia below the injury, there is excess activity of monoamine receptors on pericytes which locally constricts capillaries and reduces blood flow to ischemic levels. [32]

Pericytes are important in maintaining circulation. In a study involving adult pericyte-deficient mice, cerebral blood flow was diminished with concurrent vascular regression due to loss of both endothelia and pericytes. Significantly greater hypoxia was reported in the hippocampus of pericyte-deficient mice as well as inflammation, and learning and memory impairment. [33]

Clinical significance

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.

Hemangioma

The clinical phases of hemangioma have physiological differences, correlated with immunophenotypic profiles by Takahashi et al. During the early proliferative phase (0–12 months) the tumors express proliferating cell nuclear antigen (pericytesna), vascular endothelial growth factor (VEGF), and type IV collagenase, the former two localized to both endothelium and pericytes, and the last to endothelium. The vascular markers CD31, von Willebrand factor (vWF), and smooth muscle actin (pericyte marker) are present during the proliferating and involuting phases, but are lost after the lesion is fully involuted. [34]

Hemangiopericytoma

Image of a solitary fibrous tumour that is most likely a hemangiopericytoma. It surrounds a staghorn-shaped blood vessel, which results from the arrangement of pericytes around the vessel Solitary fibrous tumour intermed mag.jpg
Image of a solitary fibrous tumour that is most likely a hemangiopericytoma. It surrounds a staghorn-shaped blood vessel, which results from the arrangement of pericytes around the vessel

Hemangiopericytoma 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. [35]

Diabetic retinopathy

The retina of diabetic individuals often exhibits loss of pericytes, and this loss is a characteristic factor of the early stages of diabetic retinopathy. Studies have found that pericytes are essential in diabetic individuals to protect the endothelial cells of retinal capillaries. With the loss of pericytes, microaneurysms 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. [36] While it is unclear why pericytes are lost in diabetic patients, one hypothesis is that toxic sorbitol and advanced glycation end-products (AGE) accumulate in the pericytes. Because of the build-up of glucose, the polyol pathway increases its flux, and intracellular sorbitol and fructose accumulate. This leads to osmotic imbalance, which results in cellular damage. The presence of high glucose levels also leads to the buildup of AGE's, which also damage cells. [37]

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.[ citation needed ] 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 (PDGFB) is released from endothelial cells in brain vasculature and binds to the receptor PDGFRB on pericytes, initiating their proliferation and investment in the vasculature.

Immunohistochemical studies of human tissue from Alzheimer's disease and amyotrophic lateral sclerosis show pericyte loss and breakdown of the blood-brain barrier. Pericyte-deficient mouse models (which lack genes encoding steps in the PDGFB:PDGFRB signalling cascade) and have an Alzheimer's-causing mutation have exacerbated Alzheimer's-like pathology compared to mice with normal pericyte coverage and an Alzheimer's-causing mutation.

Stroke

In conditions of stroke, pericytes constrict brain capillaries and then die, which may lead to a long-lasting decrease of blood flow and loss of blood–brain barrier function, increasing the death of nerve cells. [11]

Research

Endothelial and pericyte interactions

Endothelial cells and pericytes are interdependent and failure of proper communication between the two cell types can lead to numerous human pathologies. [38]

There are several pathways of communication between the endothelial cells and pericytes. The first is transforming growth factor (TGF) signaling, which is mediated by endothelial cells. This is important for pericyte differentiation. [39] [40] Angiopoietin 1 and Tie-2 signaling is essential for maturation and stabilization of endothelial cells. [41] Platelet-derived growth factor (PDGF) pathway signaling from endothelial cells recruits pericytes, so that pericytes can migrate to developing blood vessels. If this pathway is blocked, it leads to pericyte deficiency. [42] Sphingosine-1-phosphate (S1P) signaling also aids in pericyte recruitment by communication through G protein-coupled receptors. S1P sends signals through GTPases that promote N-cadherin trafficking to endothelial membranes. This trafficking strengthens endothelial contacts with pericytes. [43]

Communication between endothelial cells and pericytes is vital. Inhibiting the PDGF pathway leads to pericyte deficiency. This causes endothelial hyperplasia, abnormal junctions, and diabetic retinopathy. [36] A lack of pericytes also causes an upregulation of vascular endothelial growth factor (VEGF), leading to vascular leakage and hemorrhage. [44] Angiopoietin 2 can act as an antagonist to Tie-2, [45] destabilizing the endothelial cells, which results in less endothelial cell and pericyte interaction. This occasionally leads to the formation of tumors. [46] Similar to the inhibition of the PDGF pathway, angiopoietin 2 reduces levels of pericytes, leading to diabetic retinopathy. [47]

Scarring

Usually, astrocytes are associated with the scarring process in the central nervous system, forming glial scars. It has been proposed that a subtype of pericytes participates in this scarring in a glial-independent manner. Through lineage tracking studies, these subtype of pericytes were followed after stroke, revealing that they contribute to the glial scar by differentiating into myofibroblasts and depositing extracellular matrix. [48] However, this remains controversial, as more recent studies suggest that the cell type followed in these scar studies is likely to be not pericytes, but fibroblasts. [49] [50]

Contribution to adult neurogenesis

The emerging evidence (as of 2019) suggests that neural microvascular pericytes, under instruction from resident glial cells, are reprogrammed into interneurons and enrich local neuronal microcircuits. [51] This response is amplified by concomitant angiogenesis.

See also

Related Research Articles

<span class="mw-page-title-main">Capillary</span> Smallest type of blood vessel

A capillary is a small blood vessel, from 5 to 10 micrometres in diameter, and is part of the microcirculation system. Capillaries are microvessels and the smallest blood vessels in the body. They are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the site of the exchange of many substances from the surrounding interstitial fluid, and they convey blood from the smallest branches of the arteries (arterioles) to those of the veins (venules). Other substances which cross capillaries include water, oxygen, carbon dioxide, urea, glucose, uric acid, lactic acid and creatinine. Lymph capillaries connect with larger lymph vessels to drain lymphatic fluid collected in microcirculation.

<span class="mw-page-title-main">Retinopathy</span> Damage to the retina of the eyes

Retinopathy is any damage to the retina of the eyes, which may cause vision impairment. Retinopathy often refers to retinal vascular disease, or damage to the retina caused by abnormal blood flow. Age-related macular degeneration is technically included under the umbrella term retinopathy but is often discussed as a separate entity. Retinopathy, or retinal vascular disease, can be broadly categorized into proliferative and non-proliferative types. Frequently, retinopathy is an ocular manifestation of systemic disease as seen in diabetes or hypertension. Diabetes is the most common cause of retinopathy in the U.S. as of 2008. Diabetic retinopathy is the leading cause of blindness in working-aged people. It accounts for about 5% of blindness worldwide and is designated a priority eye disease by the World Health Organization.

<span class="mw-page-title-main">Diabetic retinopathy</span> Diabetes-induced damage to the retina of the eye

Diabetic retinopathy, is a medical condition in which damage occurs to the retina due to diabetes. It is a leading cause of blindness in developed countries and one of the lead causes of sight loss in the world, even though there are many new therapies and improved treatments for helping people live with diabetes.

<span class="mw-page-title-main">Angiogenesis</span> Blood vessel formation, when new vessels emerge from existing vessels

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 splitting, but processes such as coalescent angiogenesis, vessel elongation and vessel cooption also play a role. Vasculogenesis is the embryonic formation of endothelial cells from mesoderm cell precursors, and from neovascularization, although discussions are not always precise. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is responsible for most, if not all, blood vessel growth during development and in disease.

<span class="mw-page-title-main">Blood–brain barrier</span> Semipermeable capillary border that allows selective passage of blood constituents into the brain

The blood–brain barrier (BBB) is a highly selective semipermeable border of endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system, thus protecting the brain from harmful or unwanted substances in the blood. The blood–brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function.

<span class="mw-page-title-main">Endothelium</span> Layer of cells that line the inner surface of blood vessels

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 wall.

Mesangial cells are specialised cells in the kidney that make up the mesangium of the glomerulus. Together with the mesangial matrix, they form the vascular pole of the renal corpuscle. The mesangial cell population accounts for approximately 30-40% of the total cells in the glomerulus. Mesangial cells can be categorized as either extraglomerular mesangial cells or intraglomerular mesangial cells, based on their relative location to the glomerulus. The extraglomerular mesangial cells are found between the afferent and efferent arterioles towards the vascular pole of the glomerulus. The extraglomerular mesangial cells are adjacent to the intraglomerular mesangial cells that are located inside the glomerulus and in between the capillaries. The primary function of mesangial cells is to remove trapped residues and aggregated protein from the basement membrane thus keeping the filter free of debris. The contractile properties of mesangial cells have been shown to be insignificant in changing the filtration pressure of the glomerulus.

<span class="mw-page-title-main">Haemodynamic response</span>

In haemodynamics, the body must respond to physical activities, external temperature, and other factors by homeostatically adjusting its blood flow to deliver nutrients such as oxygen and glucose to stressed tissues and allow them to function. Haemodynamic response (HR) allows the rapid delivery of blood to active neuronal tissues. The brain consumes large amounts of energy but does not have a reservoir of stored energy substrates. Since higher processes in the brain occur almost constantly, cerebral blood flow is essential for the maintenance of neurons, astrocytes, and other cells of the brain. This coupling between neuronal activity and blood flow is also referred to as neurovascular coupling.

Mural cells are the vascular smooth muscle cells (vSMCs), and pericytes, of the microcirculation. Both types are in close contact with the endothelial cells lining the capillaries, and are important for vascular development and stability. Mural cells are involved in the formation of normal vasculature and are responsive to factors including platelet-derived growth factor B (PDGFB) and vascular endothelial growth factor (VEGF). The weakness and disorganization of tumor vasculature is partly due to the inability of tumors to recruit properly organized mural cells.

Vascular endothelial growth factor, 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, the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis and angiogenesis.

Diabetic angiopathy is a form of angiopathy associated with diabetic complications. While not exclusive, the two most common forms are diabetic retinopathy and diabetic nephropathy, whose pathophysiologies are largely identical. Other forms of diabetic angiopathy include diabetic neuropathy and diabetic cardiomyopathy.

Neovascularization is the natural formation of new blood vessels, usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circulation in response to local poor perfusion or ischemia.

<span class="mw-page-title-main">Endothelial stem cell</span> Stem cell in bone marrow that gives rise to endothelial cells

Endothelial stem cells (ESCs) are one of three types of stem cells found in bone marrow. They are multipotent, which describes the ability to give rise to many cell types, whereas a pluripotent stem cell can give rise to all types. ESCs have the characteristic properties of a stem cell: self-renewal and differentiation. These parent stem cells, ESCs, give rise to progenitor cells, which are intermediate stem cells that lose potency. Progenitor stem cells are committed to differentiating along a particular cell developmental pathway. ESCs will eventually produce endothelial cells (ECs), which create the thin-walled endothelium that lines the inner surface of blood vessels and lymphatic vessels. The blood vessels include arteries and veins. Endothelial cells can be found throughout the whole vascular system and they also play a vital role in the movement of white blood cells

<span class="mw-page-title-main">Angiopoietin</span> Protein family

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 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 are involved with controlling microvascular permeability, vasodilation, and vasoconstriction by signaling smooth muscle cells surrounding vessels. There are now four identified angiopoietins: ANGPT1, ANGPT2, ANGPTL3, ANGPT4.

<span class="mw-page-title-main">Vascular endothelial growth factor A</span> Protein involved in blood vessel growth

Vascular endothelial growth factor A (VEGF-A) is a protein that in humans is encoded by the VEGFA gene.

Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.

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 2002 and the process was previously known as neurovascular patterning. The combination of neurogenesis and angiogenesis is an essential part of embryonic development and early life. It is thought to have a role in pathologies such as endometriosis, brain tumors, and Alzheimer's disease.

<span class="mw-page-title-main">Pathophysiology of Parkinson's disease</span> Medical condition

The pathophysiology of Parkinson's disease is death of dopaminergic neurons as a result of changes in biological activity in the brain with respect to Parkinson's disease (PD). There are several proposed mechanisms for neuronal death in PD; however, not all of them are well understood. Five proposed major mechanisms for neuronal death in Parkinson's Disease include protein aggregation in Lewy bodies, disruption of autophagy, changes in cell metabolism or mitochondrial function, neuroinflammation, and blood–brain barrier (BBB) breakdown resulting in vascular leakiness.

<span class="mw-page-title-main">Tumor-associated endothelial cell</span>

Tumor-associated endothelial cells or tumor endothelial cells (TECs) refers to cells lining the tumor-associated blood vessels that control the passage of nutrients into surrounding tumor tissue. Across different cancer types, tumor-associated blood vessels have been discovered to differ significantly from normal blood vessels in morphology, gene expression, and functionality in ways that promote cancer progression. There has been notable interest in developing cancer therapeutics that capitalize on these abnormalities of the tumor-associated endothelium to destroy tumors.

<span class="mw-page-title-main">Cellular extensions</span> Structures projecting from cells

Cellular extensions also known as cytoplasmic protrusions and cytoplasmic processes are those structures that project from different cells, in the body, or in other organisms. Many of the extensions are cytoplasmic protrusions such as the axon and dendrite of a neuron, known also as cytoplasmic processes.

References

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