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Pericyte
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
Latinpericytus
MeSHD020286
THH3.09.02.0.02006
FMA63174
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]

Structure

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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

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Skeletal muscle regeneration and fat formation

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Pericytes in the skeletal striated muscle are of two distinct populations, each with its own role.[15] 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.[16] The extent to which type-1 pericytes participate in fat accumulation is not known.

Angiogenesis and the survival of endothelial cells

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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.[17]

A lineage relationship to other cell types has been proposed, including smooth muscle cells,[18] neural cells,[18] NG2 glia,[19] muscle fibers, adipocytes, as well as fibroblasts[20] 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.[20] Such versatility is useful, as they actively remodel blood vessels throughout the body and can thereby blend homogeneously with the local tissue environment.[21]

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.[22] 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.[23] 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.[24]

Blood–brain barrier

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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.[25]

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.[26][27] Loss or dysfunction of pericytes is also theorized to contribute to neurodegenerative diseases such as Alzheimer's,[28][29][30] Parkinson's and ALS[31] through breakdown of the blood-brain barrier.

Blood flow

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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.[32] It appears that different signaling pathways regulate the constriction of capillaries by pericytes and of arterioles by smooth muscle cells.[33] 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.[34]

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.[35]

Clinical significance

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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

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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.[36]

Hemangiopericytoma

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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.[37]

Diabetic retinopathy

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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.[38] 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.[39]

Neurodegenerative diseases

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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

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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

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Endothelial and pericyte interactions

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Endothelial cells and pericytes are interdependent and failure of proper communication between the two cell types can lead to numerous human pathologies.[40]

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.[41][42] Angiopoietin 1 and Tie-2 signaling is essential for maturation and stabilization of endothelial cells.[43] 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.[44] 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.[45]

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.[38] A lack of pericytes also causes an upregulation of vascular endothelial growth factor (VEGF), leading to vascular leakage and hemorrhage.[46] Angiopoietin 2 can act as an antagonist to Tie-2,[47] destabilizing the endothelial cells, which results in less endothelial cell and pericyte interaction. This occasionally leads to the formation of tumors.[48] Similar to the inhibition of the PDGF pathway, angiopoietin 2 reduces levels of pericytes, leading to diabetic retinopathy.[49]

Scarring

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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.[50] 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.[51][52]

Contribution to adult neurogenesis

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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.[53] This response is amplified by concomitant angiogenesis.

See also

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References

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Revisions and contributorsEdit on WikipediaRead on Wikipedia

Pericyte

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Pericytes are contractile, perivascular cells that envelop the endothelial cells of capillaries and post-capillary venules throughout the body, providing and regulatory functions to the microvasculature. First described in the by researchers such as Eberth and Rouget, and formally named by in 1923, these cells exhibit a characteristic "bump-on-a-log" morphology, with elongated processes that extend along and encircle the vessel walls, and are typically identified by their expression of markers like platelet-derived growth factor receptor beta (PDGFRβ) and neural/glial antigen 2 (NG2). In physiological contexts, pericytes play critical roles in vascular , including the regulation of blood flow through contraction and relaxation mechanisms influenced by signaling molecules such as and β-adrenergic agonists. They are essential for , where they interact with endothelial cells via pathways like PDGF-B/PDGFRβ and (VEGF) to promote vessel sprouting, maturation, and stabilization, covering up to 90% of surfaces in many tissues. Additionally, pericytes contribute to barrier functions, such as maintaining the blood-brain barrier by controlling endothelial and limiting immune cell infiltration, while exhibiting multipotent stem-like properties that allow differentiation into various cell types including fibroblasts and cells. Developmentally, pericytes arise from diverse origins, including mesenchymal cells, neural crest progenitors in the central nervous system, or mesothelial cells in organs like the heart and lungs, and are recruited to nascent vessels during embryogenesis to ensure proper vascular morphogenesis. In pathological conditions, pericyte dysfunction or loss is implicated in numerous disorders, such as diabetic retinopathy where their depletion leads to vascular leakage, tissue fibrosis through differentiation into myofibroblasts, and tumor progression by altering vessel normalization in the stroma. These multifaceted roles underscore pericytes' importance as dynamic regulators of vascular integrity across health and disease.

Structure and Identification

Morphology and Distribution

Pericytes are contractile, elongated cells characterized by their slender, spindle-shaped soma and extensive cytoplasmic processes that extend longitudinally and circumferentially to partially or fully encircle the of capillaries and post-capillary venules. These processes enable pericytes to maintain close physical contact with the , while the cells themselves are embedded within the shared that surrounds the microvessel wall. This morphological arrangement positions pericytes as integral components of the microvasculature, distinct from the more circumferential found on larger arterioles and venules. The distribution and coverage density of pericytes vary significantly across tissues, reflecting specialized vascular demands. In the central nervous system (CNS), including the brain and retina, pericytes are abundant and provide extensive coverage, with typically 1 to 3 pericytes per capillary segment, contributing to the high endothelial-pericyte ratio of approximately 3:1 to 1:1. This dense arrangement supports the integrity of the blood-brain barrier (BBB). In contrast, coverage is sparser in peripheral tissues such as skeletal muscle, where pericytes are fewer and processes cover less of the endothelial surface. Overall, pericytes exhibit varying prevalence across tissues, with high density in the CNS (pericyte-to-endothelial ratio of 1:3) and intermediate in heart and lungs, but sparse in skeletal muscle (1:100), where they still contribute to the microvasculature of capillaries and small vessels, though notably sparse or absent along the walls of larger arteries and veins. Morphological subtypes of pericytes have been identified based on soma shape, process extension, and tissue-specific prevalence, with recent imaging studies elucidating their distribution. Type-1 pericytes feature a thin, elongated soma with extensive, branching that provide broad coverage along capillaries, predominating in the where they maintain vascular quiescence. Type-2 pericytes, in comparison, exhibit a bulkier soma and shorter, fewer , often located at vessel branch points, and are more common in , as confirmed by advanced fluorescent in 2025 analyses. Quantitatively, the pericyte-to-endothelial cell ratio underscores these patterns, averaging 1:100 in peripheral tissues like but reaching 1:3 in the CNS, highlighting the organ-specific adaptations in pericyte density.

Molecular Markers and Subtypes

Pericytes are primarily identified through the expression of receptor beta (PDGFRβ), a that serves as a key marker due to its role in pericyte recruitment and its broad expression across pericyte populations. NG2, also known as chondroitin sulfate proteoglycan 4 (CSPG4), is a prominent marker associated with proliferating pericytes, particularly those involved in active vascular remodeling, and exhibits high sensitivity for detection in various tissues including muscle. Contractile pericytes, which contribute to vascular tone, are characterized by the expression of desmin, an protein, and alpha-smooth muscle actin (α-SMA), a cytoskeletal component that indicates a more differentiated, smooth muscle-like phenotype. Recent research from 2025 has highlighted emerging markers that enhance pericyte detection and subtype specificity. CSPG4/NG2 remains valuable for identifying muscle-specific pericytes, supporting lineage tracing in contexts. CD146 (also known as MCAM) and CD13 ( N) are recognized as more universal markers applicable across pericyte populations, though their specificity is moderated by expression in endothelial and inflammatory cells. In the (CNS), regulator of G protein signaling 5 (RGS5) emerges as a subtype-specific marker, particularly for activated pericytes in response to hypoxia or injury models. Pericyte subtypes are classified based on marker profiles that reflect their developmental and functional states. NG2-positive (NG2+) pericytes represent a proliferative subtype linked to angiogenic processes, while pericytes expressing only PDGFRβ (without NG2 or α-SMA) denote a focused on structural support. Single-cell sequencing (scRNA-seq) studies in 2025 have further delineated heterogeneity, identifying inflammatory subtypes in cardiac tissue characterized by upregulated immune-related genes and fibrotic subtypes in both heart and brain tissues marked by production genes such as COL3A1. Common techniques for pericyte identification include (IHC), which visualizes markers like PDGFRβ and NG2 in tissue sections, and , which enables isolation of live pericytes using antibodies against CD13 or PDGFRβ from dissociated tissues. Genetic lineage tracing, such as with Pdgfrb-Cre lines, provides precise labeling of pericyte lineages from developmental stages onward, distinguishing them from vascular cells. Pericyte marker expression demonstrates significant tissue-specific heterogeneity, underscoring their adaptive roles across organs. For instance, pericytes exhibit high levels of α-SMA, particularly on segments, reflecting their contractile properties. In contrast, pulmonary pericytes, especially those in capillaries, show low α-SMA expression, with greater reliance on PDGFRβ and NG2 for identification amid their mesenchymal diversity.

Physiological Functions

Vascular Stability and Angiogenesis

Pericytes are recruited to nascent vessels during angiogenesis primarily through platelet-derived growth factor BB (PDGF-BB) secreted by endothelial cells, which binds to PDGF receptor beta (PDGFRβ) on pericytes, promoting their proliferation, migration, and attachment to stabilize sprouting capillaries. This signaling pathway ensures timely pericyte investment, preventing excessive endothelial proliferation and vascular regression in immature networks. In establishing vascular stability, pericytes contribute to the deposition of key components, including collagen IV and , which form a supportive matrix around endothelial tubes and inhibit endothelial while reducing vessel leakage. Pericyte-endothelial interactions further enhance barrier by inducing the expression of endothelial proteins, such as claudin-5, through pericyte-secreted factors like glial cell line-derived neurotrophic factor (GDNF), thereby limiting paracellular permeability. Detachment of pericytes from vessels, often due to disrupted PDGF signaling, triggers selective regression of immature branches by destabilizing endothelial cells and promoting their . During embryonic development, pericytes play an essential role in vasculogenesis by providing structural support to forming vessels, with their absence leading to widespread hemorrhaging and . For instance, Pdgfb mice exhibit near-complete loss of pericyte coverage in microvessels of the , , and other organs, resulting in dilated, leaky vessels and perinatal death around embryonic day 18 to birth. Recent research highlights pericytes as mechanical sensors that detect (ECM) stiffness changes, facilitating ECM remodeling to guide vessel branching through -mediated signaling pathways. Specifically, α8 (ITGA8) in pericytes links ECM cues to cytoskeletal dynamics via RhoA/ROCK signaling, promoting pericyte process elongation and enhanced vascular coverage that supports branching and maturation during . In the , this mechanism contributes to blood-brain barrier formation by stabilizing tight junctions like claudin-5.

Blood Flow Regulation and Barrier Maintenance

Pericytes regulate local blood flow through their contractile properties, primarily mediated by an - machinery that includes α-smooth muscle actin (α-SMA) and (MLC). This apparatus enables and in response to physiological signals, with α-SMA forming in conjunction with II to generate contractile force. Calcium-dependent signaling plays a central role, as elevations in cytosolic calcium activate , leading to MLC and enhanced actomyosin cross-bridge cycling for precise adjustment of tone. The protruding processes of pericytes encircle and function as dynamic sphincters, controlling capillary diameter to modulate . By contracting these processes, pericytes can restrict erythrocyte passage, thereby fine-tuning oxygen delivery to surrounding tissues based on metabolic demand. In the , this mechanism supports neurovascular coupling, where pericyte-mediated changes in capillary diameter can substantially increase local blood flow, with models indicating potential increases ranging from approximately 18% to 200% depending on assumptions, in response to neuronal activity, ensuring efficient nutrient supply without excessive upstream involvement. In the blood-brain barrier (BBB), pericytes contribute to maintenance by promoting the polarization of end-feet, which cover the abluminal surface of endothelial cells and pericytes to stabilize vascular integrity. They also regulate the expression of efflux transporters, such as ATP-binding cassette (ABC) transporters like , which actively exclude neurotoxic substances from the brain parenchyma. Recent 2025 studies highlight how pericyte subtypes influence -related BBB permeability, with sleep disruption linked to pericyte dysfunction that increases barrier leakage and impairs clearance of metabolites. Pericytes play an analogous role in the inner blood-retinal barrier (iBRB), where they prevent vascular leakage by stabilizing at endothelial adherens junctions during retinal vascular maturation. This interaction, facilitated by platelet-derived growth factor-B (PDGF-B)/PDGF receptor-β signaling, ensures proper organization of junctional proteins and maintains .

Tissue Regeneration and Repair

Pericytes serve as mesenchymal progenitors with multipotent differentiation potential, enabling them to contribute to tissue repair by differentiating into various cell types at injury sites. In response to damage, pericytes can transition into fibroblasts, which facilitate (ECM) remodeling, or into adipocytes and osteoblasts, supporting structural recovery in diverse tissues. This plasticity is driven by their perivascular location and responsiveness to growth factors like (), allowing them to migrate and adapt to local cues during . In , NG2+ pericytes play a key role in regeneration by supporting satellite cell activation and contributing to myofiber formation following . These pericytes, identified by the NG2 marker, differentiate into muscle fibers and integrate into the satellite cell pool, enhancing repair efficiency in models of acute damage such as cardiotoxin-induced , where they account for up to 11% of new fibers in certain muscles. Their involvement ensures coordinated , with NG2+ cells promoting postnatal muscle growth and recovery without fully replacing satellite cells. Within , pericytes act as progenitors, differentiating into new fat cells during conditions like or to accommodate tissue expansion or repair. PDGFRβ+ pericytes contribute to the formation of new white in gonadal fat under high-fat diet-induced , while NG2+ subtypes generate up to 50% of in subcutaneous white fat following cold exposure or damage, aiding metabolic adaptation. This process involves signaling pathways like PPARγ activation, which favors over other lineages in stressed adipose environments. Pericytes exhibit immunomodulatory functions by interacting with immune cells to support tissue homeostasis during regeneration. Pericytes also drive ECM deposition essential for closure but can exacerbate in chronic injuries through TGF-β signaling. In normal healing, they differentiate into myofibroblasts that deposit types I and III, stabilizing the bed via TGF-β-induced contraction and matrix synthesis. However, in persistent , such as cerebral small vessel disease, TGF-β1 activates pericytes via SMAD3/IL-11 pathways, leading to excessive ECM accumulation and fibrotic scarring, as seen in increased I in hypoperfused tissues.

Pathophysiological Roles

Diabetic Retinopathy and Retinal Vascular Diseases

Pericyte apoptosis represents an early hallmark of diabetic retinopathy (DR), triggered by hyperglycemia, which subsequently leads to the formation of acellular capillaries and microaneurysms in the retinal vasculature. In diabetic models, sustained high glucose levels induce pericyte death through caspase-3 activation and DNA fragmentation, observable within weeks of hyperglycemia onset. This selective pericyte loss, documented histologically over seven decades ago, precedes endothelial cell damage and correlates with the initial microvascular abnormalities in human DR retinas. As pericyte coverage diminishes, retinal microvessels become unstable, resulting in inner blood-retina barrier (iBRB) breakdown, , and pathological neovascularization. Reduced pericyte-endothelial interactions impair integrity, increasing and allowing plasma leakage into retinal tissues. In non-proliferative DR, this manifests as capillary non-perfusion and , while in proliferative stages, hypoxia-driven exacerbates vision-threatening complications like vitreous hemorrhage. Pericyte deficiency thus accelerates the transition from early vasodegeneration to advanced proliferative disease. The underlying mechanisms involve oxidative stress and advanced glycation end-products (AGEs), which promote pericyte apoptosis via protein kinase C (PKC) activation and vascular endothelial growth factor (VEGF) dysregulation. Hyperglycemia elevates reactive oxygen species (ROS), activating PKC-δ isoforms that suppress platelet-derived growth factor (PDGF) signaling and induce pericyte detachment from endothelium. AGEs bind to receptors on pericytes, further amplifying ROS and PKC pathways, leading to NF-κB-mediated inflammation and excessive VEGF expression that disrupts barrier function. These pathways collectively drive pericyte loss and sustain the inflammatory milieu in DR. Recent 2025 research highlights 's role in preserving retinal pericytes through , specifically by suppressing tumor necrosis factor-α (TNF-α) in proliferative models. inhibits microglial activation and TNF-α release, reducing pericyte and vascular leakage in DR, offering a potential adjunct to therapies. Beyond DR, pericytes contribute to other retinal vascular diseases via analogous leakage mechanisms. In (ROP), hyperoxia-induced pericyte migration and dropout destabilize nascent vessels, promoting avascular zones and subsequent neovascular proliferation with barrier compromise. Similarly, in age-related (AMD), pericyte correlates with and macular leakage, as lower capillary pericyte density predicts increased in atrophic AMD lesions.

Neurodegenerative Diseases and Cognitive Decline

Pericytes play a critical role in the pathogenesis of (AD) through their involvement in amyloid-β (Aβ) clearance and vascular stability. Degeneration of brain pericytes reduces the uptake and degradation of Aβ aggregates via receptors such as low-density lipoprotein receptor-related protein 1 (LRP1), leading to accumulation of Aβ in the brain parenchyma and exacerbation of . This pericyte loss also promotes tau hyperphosphorylation and neurodegeneration in Aβ-precursor protein-overexpressing mouse models, highlighting pericytes' control over multiple steps in the AD pathogenic cascade. Furthermore, Aβ interacts with pericytes to induce their constriction, detachment, and , perpetuating vascular dysfunction and Aβ buildup. Loss of pericyte coverage impairs the blood-brain barrier (BBB), increasing its permeability to neurotoxins, inflammatory molecules, and immune cells, which accelerates neurodegeneration and cognitive decline. In normal physiology, pericytes maintain BBB integrity by supporting endothelial tight junctions and limiting paracellular transport, but their deficiency in disrupts this barrier function. Pericyte degeneration elevates Aβ levels by hindering clearance pathways, including pericyte-mediated and . Recent 2025 studies have identified pericyte subtypes, such as matrix-associated (M-)pericytes, as key regulators of -dependent glymphatic clearance; sleep fragmentation correlates with M-pericyte dysfunction, reduced Aβ removal during sleep, and faster cognitive decline in older adults with and without . In (PD), pericytes contribute to by internalizing and degrading α-synuclein aggregates but ultimately succumbing to overload, releasing pro-inflammatory mediators that promote BBB leakage and α-synuclein spread via tunneling nanotubes to and . This pericyte-mediated exacerbates loss and motor symptoms in PD models. Similarly, in (ALS), pericyte reductions disrupt the blood-spinal cord barrier, leading to and impaired neurotrophic support, such as loss of pericyte-derived pleiotrophin, which contributes to degeneration. TDP-43 pathology in ALS further drives pericyte loss, amplifying barrier breakdown and neuroinflammatory cascades that hasten death. Pericyte dysfunction underlies vascular cognitive impairment (VCI) by causing hypoperfusion through failed contractility, resulting in chronic ischemia and damage. In aging brains, deficient pericyte remodeling leads to persistent dilation and reduced cerebral blood flow, particularly in tracts, promoting demyelination and axonal injury that manifest as . Pericyte contraction, regulated by calcium channels, is impaired early in disease models, trapping leukocytes and worsening hypoxia in vulnerable regions. Epidemiological evidence links pericyte density to risk in aging populations, with reduced pericyte coverage inversely correlating with BBB leakage and cognitive decline across cohorts. In human studies, lower pericyte-to-endothelial ratios in aged brains predict higher incidence, independent of or pathology, emphasizing vascular factors as modifiable risks. Pericyte loss, a hallmark of normal aging, amplifies susceptibility to in longitudinal analyses of older adults.

Stroke and Ischemic Injury

In the acute phase of , pericytes rapidly constrict capillaries in response to ischemia, a mediated by elevated intracellular calcium and ATP signaling, which limits hemorrhage by reducing blood flow but exacerbates tissue hypoxia and contributes to the no-reflow phenomenon upon reperfusion. This constriction persists even after recanalization, impeding microvascular perfusion and promoting secondary injury. Concurrently, pericytes migrate toward the injury site, driven by matrix metalloproteinase-9 (MMP-9) activation and platelet-derived growth factor-B (PDGF-B)/PDGF receptor-β (PDGFRβ) signaling, where they detach from the and contribute to early inflammatory responses. Pericyte detachment from the vascular wall, occurring within the first hour of ischemia, disrupts blood-brain barrier (BBB) integrity by degrading tight junctions and components via upregulated MMP-2 and MMP-9 secretion, leading to vasogenic , leukocyte infiltration, and amplified secondary neuronal . This pericyte-endothelial uncoupling further promotes and paracellular leakage, intensifying infarct expansion in the peri-infarct zone. During the recovery phase, PDGFRβ+ pericytes transition into myofibroblast-like cells that deposit proteins, such as , to form fibrotic glial scars that seal the lesion core and prevent further tissue degradation, thereby supporting peri-infarct , oligodendrogenesis, and functional restoration through enhanced myelination and . Recent 2025 analyses highlight the bidirectional nature of this role, where pericytes provide via secretion of (VEGF) and of debris as microglia-like cells, yet excessive from their differentiation can impede axonal regrowth and long-term recovery. In ischemic models, such as those using PDGFRβ heterozygous mice or pharmacological , pericyte loss results in 2- to 3-fold larger infarct volumes due to impaired vascular stability and BBB protection, underscoring their essential function in limiting damage.00824-X) Similar pericyte dynamics occur in cardiac ischemia, particularly in microinfarcts, where they constrict coronary capillaries post-ischemia to restrict hemorrhage but hinder reperfusion, while also modulating collateral vessel formation and remodeling to restore myocardial blood flow during recovery.

Research Directions

Pericyte-Endothelial and Glial Interactions

Pericytes maintain vascular integrity through bidirectional signaling with endothelial cells, particularly via the Notch3-Jagged1 pathway, which promotes pericyte maturation and proliferation during vessel development. Endothelial cells express Jagged1, a Notch , which activates Notch3 receptors on pericytes to enhance their contractile properties and to the , thereby stabilizing nascent vessels. This interaction is essential for pericyte-induced endothelial quiescence, preventing excessive sprouting and ensuring proper vascular patterning. Additionally, VEGF/PDGF signaling loops orchestrate pericyte recruitment, where endothelial-derived PDGF-BB binds PDGFRβ on pericytes to direct their migration and along vessels, while pericytes in turn secrete VEGF to support endothelial and proliferation during . These loops create a feedback mechanism that balances vessel growth and maturation, with disruptions leading to abnormal pericyte coverage. Pericytes also interact closely with glial cells to support neurovascular unit function, as evidenced by research as of 2025 demonstrating pericyte-astrocyte coupling that maintains blood-brain barrier integrity and facilitates neurovascular coupling in the brain, including regulation of aquaporin-4 polarization and cerebral blood flow via signaling. Astrocytes extend endfeet that envelop pericyte-covered capillaries, enabling pericytes to regulate astrocyte polarization and homeostasis through shared signaling pathways like TGF-β. In parallel, pericytes modulate microglial responses to via /fractalkine signaling, where pericyte-associated fractalkine ligands interact with CX3CR1 receptors on to attenuate pro-inflammatory activation and promote vascular protection. These glial interactions underscore pericytes' role in coordinating immune surveillance and barrier maintenance within the neurovascular niche, with 2025 studies highlighting gliovascular transcriptomic changes such as perturbed SMAD3-VEGFA interactions in . In vitro co-culture models have elucidated these mechanisms, showing that pericytes induce endothelial quiescence by suppressing proliferative genes and upregulating proteins such as ZO-1, which enhances barrier permeability resistance. For instance, triple co-cultures of endothelial cells, pericytes, and demonstrate increased ZO-1 expression and reduced paracellular leakage compared to endothelial monocultures, mimicking neurovascular unit dynamics. Such studies highlight pericyte-derived factors like Ang-1 that reinforce endothelial junctions and quiescence. In neurodegenerative contexts, disrupted pericyte-endothelial and glial interactions contribute to , with pericyte loss impairing endfoot polarization and leading to blood-brain barrier leakage. This detachment reduces astrocyte coverage of vessels and exacerbates neuroinflammatory signaling, as pericytes normally guide glial polarization via contact-dependent cues. Quantitative aspects of these interactions are further illustrated by PDGF-BB gradients, which spatially direct pericyte coverage density; steeper gradients from endothelial sources correlate with higher pericyte investment (up to 80-90% coverage in mature vessels), ensuring uniform vascular stability. Basic markers such as PDGFRβ and NG2, often used in these interaction studies, confirm pericyte identity without altering the core signaling dynamics.

Therapeutic Targeting and Subtype-Specific Roles

Recent single-cell RNA sequencing studies have identified distinct pericyte subpopulations with potential therapeutic implications, particularly in oncology and fibrosis. For instance, analysis of cancer-associated pericytes (CAPs) in tumor microenvironments revealed subtypes linked to prognosis, suggesting they as biomarkers and targets for intervention. In pulmonary tissues, HIGD1B+ pericyte subtypes were delineated, with type 1 pericytes showing hypoxia-induced changes that could inform anti-angiogenic strategies. Targeting NG2+ pericytes, which express the NG2 proteoglycan on angiogenic vessels, has shown promise in reducing pathological angiogenesis; NG2 ligands delivered via peptides inhibited tumor vascularization in preclinical models. Similarly, PDGFRβ inhibitors attenuate pericyte-myofibroblast transition in fibrotic conditions, such as idiopathic pulmonary fibrosis (IPF), where PDGFRβ+ pericytes drive excessive extracellular matrix deposition; inhibition in rodent models reduced fibrosis progression. Pericytes serve as gatekeepers in the blood-brain barrier (BBB), influencing permeability and offering opportunities for nanoparticle-based in neurodegenerative diseases. Their role in maintaining BBB integrity means disruptions, common in conditions like Alzheimer's, can be exploited for targeted therapies; engineered cross compromised BBBs to deliver neuroprotective agents directly to affected regions. In neurodegeneration, pericyte loss exacerbates vascular leakage, and nanoparticle strategies aim to restore function by enhancing across the BBB. Preclinical evidence supports pericyte-targeted nanoparticles to mitigate and accumulation. Clinical translation of pericyte-targeted therapies is advancing, with PDGFR inhibitors like demonstrating efficacy in preclinical models of by suppressing pericyte loss and neovascularization. reduced VEGF and FGF2 expression, limiting retinal vascular pathology in oxygen-induced retinopathy models. For , has shown neuroprotective effects in preclinical and phase II trials, preserving vascular integrity post-ischemia via anti-inflammatory mechanisms and blood-brain barrier protection. A phase III trial as of 2025 is evaluating its efficacy in improving functional outcomes. In , pericytes contribute to the hippocampal subgranular zone niche, supporting maintenance and differentiation; this positions them as targets for cognitive repair therapies in aging or trauma. Co-culture models confirm pericytes secrete factors that enhance proliferation. Pericyte heterogeneity poses challenges to precise targeting, as inflammatory responses vary by subtype, age, and species, complicating uniform therapeutic responses. targeting inflammatory pericytes has improved in diabetic models by correcting . These tools address heterogeneity by allowing selective modulation of pro-fibrotic or pro-angiogenic pathways in NG2+ or PDGFRβ+ subsets, paving the way for personalized interventions.

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