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Developmental Cell Aug 2011Pericytes, the mural cells of blood microvessels, have recently come into focus as regulators of vascular morphogenesis and function during development, cardiovascular... (Review)
Review
Pericytes, the mural cells of blood microvessels, have recently come into focus as regulators of vascular morphogenesis and function during development, cardiovascular homeostasis, and disease. Pericytes are implicated in the development of diabetic retinopathy and tissue fibrosis, and they are potential stromal targets for cancer therapy. Some pericytes are probably mesenchymal stem or progenitor cells, which give rise to adipocytes, cartilage, bone, and muscle. However, there is still confusion about the identity, ontogeny, and progeny of pericytes. Here, we review the history of these investigations, indicate emerging concepts, and point out problems and promise in the field of pericyte biology.
Topics: Animals; Cell Differentiation; Collagen Type IV; Endothelium, Vascular; Models, Biological; Neovascularization, Pathologic; Neovascularization, Physiologic; Pericytes; Signal Transduction
PubMed: 21839917
DOI: 10.1016/j.devcel.2011.07.001 -
Journal of Cerebral Blood Flow and... Feb 2016Pericytes, spatially isolated contractile cells on capillaries, have been reported to control cerebral blood flow physiologically, and to limit blood flow after... (Review)
Review
Pericytes, spatially isolated contractile cells on capillaries, have been reported to control cerebral blood flow physiologically, and to limit blood flow after ischaemia by constricting capillaries and then dying. Paradoxically, a recent paper dismisses the idea of pericytes controlling cerebral blood flow, despite confirming earlier data showing a role for pericytes. We show that these discrepancies are apparent rather than real, and depend on the new paper defining pericytes differently from previous reports. An objective definition of different sub-classes of pericyte along the capillary bed is needed to develop novel therapeutic approaches for stroke and disorders caused by pericyte malfunction.
Topics: Animals; Capillaries; Cerebrovascular Circulation; Humans; Pericytes; Terminology as Topic
PubMed: 26661200
DOI: 10.1177/0271678X15610340 -
Cancer Letters Mar 2023Pericytes are a type of mural cell located between the endothelial cells of capillaries and the basement membrane, which function to regulate the capillary vasomotor and... (Review)
Review
Pericytes are a type of mural cell located between the endothelial cells of capillaries and the basement membrane, which function to regulate the capillary vasomotor and maintain normal microcirculation of local tissues and organs and have been identified as a significant component in the tumor microenvironment (TME). Pericytes have various interactions with different components of the TME, such as constituting the pre-metastatic niche, promoting the growth of cancer cells and drug resistance through paracrine activity, and inducing M2 macrophage polarization. While changes in the TME can affect the number, phenotype, and molecular markers of pericytes. For example, pericyte detachment from endothelial cells in the TME facilitates tumor cells in situ to invade the circulating blood and is beneficial to local capillary basement membrane enzymatic hydrolysis and endothelial cell proliferation and budding, which contribute to tumor angiogenesis and metastasis. In this review, we discuss the emerging role of pericytes in the TME, and tumor treatment related to pericytes. This review aimed to provide a more comprehensive understanding of the function of pericytes and the relationship between pericytes and tumors and to provide ideas for the treatment and prevention of malignant tumors.
Topics: Humans; Pericytes; Tumor Microenvironment; Endothelial Cells; Macrophages; Neovascularization, Pathologic; Neoplasms
PubMed: 36682706
DOI: 10.1016/j.canlet.2023.216074 -
International Journal of Molecular... Oct 2020Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the... (Review)
Review
Retinal microvasculature is crucial for the visual function of the neural retina. Pericytes and endothelial cells (ECs) are the two main cellular constituents in the retinal microvessels. Formation, maturation, and stabilization of the micro-vasculatures require pericyte-endothelial interactions, which are perturbed in many retinal vascular disorders, such as retinopathy of prematurity, retinal vein occlusion, and diabetic retinopathy. Understanding the cellular and molecular mechanisms of pericyte-endothelial interaction and perturbation can facilitate the design of therapeutic intervention for the prevention and treatment of retinal vascular disorders. Pericyte-endothelial interactions are indispensable for the integrity and functionality of retinal neurovascular unit (NVU), including vascular cells, retinal neurons, and glial cells. The essential autocrine and paracrine signaling pathways, such as Vascular endothelial growth factor (VEGF), Platelet-derived growth factor subunit B (PDGFB), Notch, Angipointein, Norrin, and Transforming growth factor-beta (TGF-β), have been well characterized for the regulation of pericyte-endothelial interactions in the neo-vessel formation processes (vasculogenesis and angiogenesis) during embryonic development. They also play a vital role in stabilizing and remodeling mature vasculature under pathological conditions. Awry signals, aberrant metabolisms, and pathological conditions, such as oxidative stress and inflammation, can disrupt the communication between pericytes and endothelial cells, thereby resulting in the breakdown of the blood-retinal barrier (BRB) and other microangiopathies. The emerging evidence supports extracellular exosomes' roles in the (mis)communications between the two cell types. This review summarizes the essential knowledge and updates about new advancements in pericyte-EC interaction and communication, emphasizing the retinal microvasculature.
Topics: Animals; Blood-Retinal Barrier; Endothelial Cells; Exosomes; Humans; Microvessels; Models, Animal; Neovascularization, Physiologic; Pericytes; Retina; Retinal Diseases; Retinal Vessels; Signal Transduction
PubMed: 33049983
DOI: 10.3390/ijms21197413 -
Nature Communications Jul 2017The Tie receptors with their Angiopoietin ligands act as regulators of angiogenesis and vessel maturation. Tie2 exerts its functions through its supposed...
The Tie receptors with their Angiopoietin ligands act as regulators of angiogenesis and vessel maturation. Tie2 exerts its functions through its supposed endothelial-specific expression. Yet, Tie2 is also expressed at lower levels by pericytes and it has not been unravelled through which mechanisms pericyte Angiopoietin/Tie signalling affects angiogenesis. Here we show that human and murine pericytes express functional Tie2 receptor. Silencing of Tie2 in pericytes results in a pro-migratory phenotype. Pericyte Tie2 controls sprouting angiogenesis in in vitro sprouting and in vivo spheroid assays. Tie2 downstream signalling in pericytes involves Calpain, Akt and FOXO3A. Ng2-Cre-driven deletion of pericyte-expressed Tie2 in mice transiently delays postnatal retinal angiogenesis. Yet, Tie2 deletion in pericytes results in a pronounced pro-angiogenic effect leading to enhanced tumour growth. Together, the data expand and revise the current concepts on vascular Angiopoietin/Tie signalling and propose a bidirectional, reciprocal EC-pericyte model of Tie2 signalling.
Topics: Animals; Cells, Cultured; Female; Human Umbilical Vein Endothelial Cells; Humans; Male; Mice, Inbred C57BL; Mice, SCID; Neovascularization, Pathologic; Neovascularization, Physiologic; Pericytes; Receptor, TIE-2; Ribonuclease, Pancreatic
PubMed: 28719590
DOI: 10.1038/ncomms16106 -
Theranostics 2023Capillary dysfunction has been implicated in a series of life- threatening vascular diseases characterized by pericyte and endothelial cell (EC) degeneration. However,...
Capillary dysfunction has been implicated in a series of life- threatening vascular diseases characterized by pericyte and endothelial cell (EC) degeneration. However, the molecular profiles that govern the heterogeneity of pericytes have not been fully elucidated. Single-cell RNA sequencing was conducted on oxygen-induced proliferative retinopathy (OIR) model. Bioinformatics analysis was conducted to identify specific pericytes involved in capillary dysfunction. qRT-PCRs and western blots were conducted to detect Col1a1 expression pattern during capillary dysfunction. Matrigel co-culture assays, PI staining, and JC-1 staining was conducted to determine the role of Col1a1 in pericyte biology. IB4 and NG2 staining was conducted to determine the role of Col1a1 in capillary dysfunction. We constructed an atlas of > 76,000 single-cell transcriptomes from 4 mouse retinas, which could be annotated to 10 distinct retinal cell types. Using the sub-clustering analysis, we further characterized retinal pericytes into 3 different subpopulations. Notably, GO and KEGG pathway analysis demonstrated that pericyte sub-population 2 was identified to be vulnerable to retinal capillary dysfunction. Based on the single-cell sequencing results, Col1a1 was identified as a marker gene of pericyte sub-population 2 and a promising therapeutic target for capillary dysfunction. Col1a1 was abundantly expressed in pericytes and its expression was obviously upregulated in OIR retinas. Col1a1 silencing could retard the recruitment of pericytes toward endothelial cells and aggravated hypoxia-induced pericyte apoptosis . Col1a1 silencing could reduce the size of neovascular area and avascular area in OIR retinas and suppressed pericyte-myofibroblast transition and endothelial-mesenchymal transition. Moreover, Col1a1 expression was up-regulated in the aqueous humor of the patients with proliferative diabetic retinopathy (PDR) or retinopathy of prematurity (ROP) and up-regulated in the proliferative membranes of PDR patients. These findings enhance the understanding of the complexity and heterogeneity of retinal cells and have important implications for future treatment of capillary dysfunction.
Topics: Mice; Animals; Pericytes; Endothelial Cells; Retina; Diabetic Retinopathy; Sequence Analysis, RNA
PubMed: 37215579
DOI: 10.7150/thno.83532 -
Gut Apr 2023Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in...
OBJECTIVE
Haematogenous dissemination is a prevalent route of colorectal cancer (CRC) metastasis. However, as the gatekeeper of vessels, the role of tumour pericytes (TPCs) in haematogenous metastasis remains largely unknown. Here, we aimed to investigate the heterogeneity of TPCs and their effects on CRC metastasis.
DESIGN
TPCs were isolated from patients with CRC with or without liver metastases and analysed by single-cell RNA sequencing (scRNA-seq). Clinical CRC specimens were collected to analyse the association between the molecular profiling of TPCs and CRC metastasis. RNA-sequencing, chromatin immunoprecipitation-sequencing and bisulfite-sequencing were performed to investigate the TCF21-regulated genes and mechanisms underlying integrin α5 on DNA hypermethylation. Pericyte-conditional -knockout mice were constructed to investigate the effects of TCF21 in TPCs on CRC metastasis. Masson staining, atomic force microscopy, second-harmonic generation and two-photon fluorescence microscopy were employed to observe perivascular extracellular matrix (ECM) remodelling.
RESULTS
Thirteen TPC subpopulations were identified by scRNA-seq. A novel subset of TCF21 TPCs, termed 'matrix-pericytes', was associated with liver metastasis in patients with CRC. TCF21 in TPCs increased perivascular ECM stiffness, collagen rearrangement and basement membrane degradation, establishing a perivascular metastatic microenvironment to instigate colorectal cancer liver metastasis (CRCLM). depletion in TPCs mitigated perivascular ECM remodelling and CRCLM, whereas the coinjection of TCF21 TPCs and CRC cells markedly promoted CRCLM. Mechanistically, loss of integrin α5 inhibited the FAK/PI3K/AKT/DNMT1 axis to impair DNA hypermethylation in TCF21 TPCs.
CONCLUSION
This study uncovers a previously unidentified role of TPCs in haematogenous metastasis and provides a potential diagnostic marker and therapeutic target for CRC metastasis.
Topics: Animals; Mice; Cell Line, Tumor; Colorectal Neoplasms; DNA; Gene Expression Regulation, Neoplastic; Integrin alpha5; Liver Neoplasms; Neoplasm Metastasis; Pericytes; Phosphatidylinositol 3-Kinases; Tumor Microenvironment
PubMed: 36805487
DOI: 10.1136/gutjnl-2022-327913 -
Circulation Research Feb 2021Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described...
RATIONALE
Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.
OBJECTIVE
To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.
METHODS AND RESULTS
We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.
CONCLUSIONS
By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.
Topics: Animals; Blood-Brain Barrier; Cell Proliferation; Cells, Cultured; Endothelial Cells; Lymphokines; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Pericytes; Platelet-Derived Growth Factor; Single-Cell Analysis; Transcriptome
PubMed: 33375813
DOI: 10.1161/CIRCRESAHA.120.317473 -
Theranostics 2022Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological...
Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. -methyladenosine (mA) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of mA RNA modification in pericyte dysfunction is still unclear. Quantitative polymerase chain reactions and western blots were conducted to detect the change of mA RNA modification in pericytes and mouse retinas following diabetic stress. MTT assay, transwell migration assay, caspase 3/7 activity assay, calcein-AM/propidium iodide (PI) staining, and TUNEL staining were conducted to determine the role of METTL3 in pericyte biology . Retinal trypsin digestion, vascular permeability assay, and IB4-NG2 double immunofluorescent staining were conducted to determine the role of METTL3 in retinal pericyte dysfunction and vascular complication. RNA sequencing, RNA pull-down assays and immunoblots were conducted to clarify the mechanism of METTL3-mediated pericyte dysfunction and vascular complication. The levels of mA RNA methylation were significantly up-regulated in pericytes and mouse retinas following diabetic stress, which were caused by increased expression of METTL3. METTL3 regulated the viability, proliferation, and differentiation of pericytes . Specific depletion of METTL3 in pericytes suppressed diabetes-induced pericyte dysfunction and vascular complication . METTL3 overexpression impaired pericyte function by repressing PKC-η, FAT4, and PDGFRA expression, which was mediated by YTHDF2-dependent mRNA decay. METTL3-mediated mA methylation epigenetically regulates diabetes-induced pericyte dysfunction. METTL3-YTHDF2-PKC-η/FAT4/PDGFRA signaling axis could be therapeutically targeted for treating microvascular complications.
Topics: Animals; Cell Line; Diabetes Mellitus; Diabetic Retinopathy; Humans; Methyltransferases; Mice; Mice, Inbred C57BL; Mice, Knockout; Pericytes
PubMed: 34987645
DOI: 10.7150/thno.63441 -
Nature Apr 2014Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging....
Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.
Topics: Animals; Arterioles; Blood-Brain Barrier; Brain Ischemia; Capillaries; Cell Death; Cerebellum; Cerebral Cortex; Cerebrovascular Circulation; Dinoprostone; Excitatory Amino Acid Antagonists; Female; Functional Neuroimaging; Glutamic Acid; Hydroxyeicosatetraenoic Acids; In Vitro Techniques; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Pericytes; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Glutamate; Signal Transduction; Stroke; Vasoconstriction; Vasodilation
PubMed: 24670647
DOI: 10.1038/nature13165