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Ira M Herman - One of the best experts on this subject based on the ideXlab platform.
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pericyte contractility controls endothelial cell cycle progression and sprouting insights into angiogenic switch mechanics
American Journal of Physiology-cell Physiology, 2014Co-Authors: Jennifer T Durham, Brian M Dulmovits, Howard K Surks, Ira M HermanAbstract:Microvascular stability and regulation of capillary tonus are regulated by Pericytes and their interactions with endothelial cells (EC). While the RhoA/Rho kinase (ROCK) pathway has been implicated in modulation of pericyte contractility, in part via regulation of the myosin light chain phosphatase (MLCP), the mechanisms linking Rho GTPase activity with actomyosin-based contraction and the cytoskeleton are equivocal. Recently, the myosin phosphatase-RhoA-interacting protein (MRIP) was shown to mediate the RhoA/ROCK-directed MLCP inactivation in vascular smooth muscle. Here we report that MRIP directly interacts with the β-actin-specific capping protein βcap73. Furthermore, manipulation of MRIP expression influences pericyte contractility, with MRIP silencing inducing cytoskeletal remodeling and cellular hypertrophy. MRIP knockdown induces a repositioning of βcap73 from the leading edge to stress fibers; thus MRIP-silenced Pericytes increase F-actin-driven cell spreading twofold. These hypertrophied and cytoskeleton-enriched Pericytes demonstrate a 2.2-fold increase in contractility upon MRIP knockdown when cells are plated on a deformable substrate. In turn, silencing pericyte MRIP significantly affects EC cycle progression and angiogenic activation. When MRIP-silenced Pericytes are cocultured with capillary EC, there is a 2.0-fold increase in EC cycle entry. Furthermore, in three-dimensional models of injury and repair, silencing pericyte MRIP results in a 1.6-fold elevation of total tube area due to EC network formation and increased angiogenic sprouting. The pivotal role of MRIP expression in governing pericyte contractile phenotype and endothelial growth should lend important new insights into how chemomechanical signaling pathways control the “angiogenic switch” and pathological angiogenic induction.
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microvascular remodeling and wound healing a role for Pericytes
The International Journal of Biochemistry & Cell Biology, 2012Co-Authors: Brian M Dulmovits, Ira M HermanAbstract:Physiologic wound healing is highly dependent on the coordinated functions of vascular and non-vascular cells. Resolution of tissue injury involves coagulation, inflammation, formation of granulation tissue, remodeling and scarring. Angiogenesis, the growth of microvessels the size of capillaries, is crucial for these processes, delivering blood-borne cells, nutrients and oxygen to actively remodeling areas. Central to angiogenic induction and regulation is microvascular remodeling, which is dependent upon capillary endothelial cell and pericyte interactions. Despite our growing knowledge of pericyte-endothelial cell crosstalk, it is unclear how the interplay among Pericytes, inflammatory cells, glia and connective tissue elements shape microvascular injury response. Here, we consider the relationships that Pericytes form with the cellular effectors of healing in normal and diabetic environments, including repair following injury and vascular complications of diabetes, such as diabetic macular edema and proliferative diabetic retinopathy. In addition, Pericytes and stem cells possessing "pericyte-like" characteristics are gaining considerable attention in experimental and clinical efforts aimed at promoting healing or eradicating ocular vascular proliferative disorders. As the origin, identification and characterization of microvascular pericyte progenitor populations remains somewhat ambiguous, the molecular markers, structural and functional characteristics of Pericytes will be briefly reviewed.
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jagged1 signaling regulates hemangioma stem cell to pericyte vascular smooth muscle cell differentiation
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Elisa Boscolo, Ira M Herman, Camille L Stewart, Shoshana Greenberger, Jennifer T Durham, John B Mulliken, Jan Kitajewski, Joyce BischoffAbstract:Objective— The aim of our study is to determine the cellular and molecular origin for the Pericytes in infantile hemangioma (IH) and their functional role in the formation of pathological blood vessels. Methods and Results— Here we show that IH-derived stem cells (HemSCs) form pericyte-like cells. With in vitro studies, we demonstrate that HemSC-to-pericyte differentiation depends on direct contact with endothelial cells. JAGGED1 expressed ectopically in fibroblasts was sufficient to induce HemSCs to acquire a pericyte-like phenotype, indicating a critical role for JAGGED1. In vivo, we blocked pericyte differentiation with recombinant JAGGED1, and we observed reduced formation of blood vessels, with an evident lack of Pericytes. Silencing JAGGED1 in the endothelial cells reduced blood vessel formation and resulted in a paucity of Pericytes. Conclusion— Our data show that endothelial JAGGED1 controls HemSC-to-pericyte differentiation in a murine model of IH and suggests that Pericytes have a fundamental role in formation of blood vessels in IH.
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pericyte rho gtpase mediates both pericyte contractile phenotype and capillary endothelial growth state
American Journal of Pathology, 2007Co-Authors: Matthew E Kutcher, Alexey Y Kolyada, Howard K Surks, Ira M HermanAbstract:Pericytes regulate microvascular development and maturation through the control of endothelial cell motility, proliferation, and differentiation. The Rho GTPases have recently been described as key regulators of pericyte shape and contractile phenotype by signaling through the actin cytoskeleton in an isoactin-specific manner. In this report, we reveal that Rho GTPase-dependent signal transduction not only influences pericyte shape and contractile potential but also modulates capillary endothelial proliferative status and pericyte-endothelial interactions in vitro. We provide evidence that overexpression of mutant Rho GTPases, but not other Ras-related small GTPases, significantly alters pericyte shape, contractility, and endothelial growth state in microvascular cell co-cultures. In particular, we describe the use of a silicon substrate deformation assay to demonstrate that pericyte contractility is Rho GTP- and Rho kinase-dependent; further, we describe a novel in vitro system for examining pericyte-mediated endothelial growth arrest and show that control Pericytes are capable of growth-arresting capillary endothelial cells in a cell contact-dependent manner, whereas Pericytes overexpressing dominant-active and -negative Rho GTPase are comparably incompetent. These data strongly suggest that signaling through the pericyte Rho GTPase pathway may provide critical cues to the processes of microvascular stabilization, maturation, and contractility during development and disease.
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tgf β1 signaling controls retinal pericyte contractile protein expression
Microvascular Research, 2003Co-Authors: Gregory J Sieczkiewicz, Ira M HermanAbstract:To define the role of transforming growth factor-β1 (TGF-β1) in modulating pericyte contractile phenotype, we have ablated the TGF-β signaling pathway by infection with a retrovirus bearing a TGF-β type II receptor with a truncated C-terminal intracellular kinase domain (DNTβRII). While TGF-β1 blocks pericyte proliferation and induces the expression of vascular smooth muscle contractile proteins in wild-type Pericytes, DNTβRII-bearing Pericytes are neither growth inhibited by TGF-β1 nor do they accumulate α-smooth muscle actin (α-SMA) mRNA or protein. TGF-β1 induces expression of the myogenic transcription factor myf-5 and the cyclin-dependent kinase inhibitor p27; we show that these signaling pathways are disrupted in the DNTβRII-bearing Pericytes. These observations demonstrate that the TGF-β1 signaling pathway controls pericyte growth state and contractile phenotype.
Christer Betsholtz - One of the best experts on this subject based on the ideXlab platform.
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Role of Pericytes in Vascular Biology
Experimental Approaches to Diabetic Retinopathy, 2009Co-Authors: Annika Armulik, Christer BetsholtzAbstract:Pericytes are obligatory constituents of blood microvessels and important regulators of blood vessel development and function. Analysis of mouse genetic mutants for factors that regulate pericyte recruitment has demonstrated the importance of Pericytes for vessel remodeling, maturation and stabilization. Such studies have also shown that impairments of one vessel wall cell type, endothelial or pericyte, will inevitably affect the other. However, we still lack a detailed understanding of the identity of pericyte-derived signals and their mechanism of action. Recent evidence suggests that Pericytes may also have important homeostatic functions in the adult vasculature. In the present review, we summarize work that has broadened our understanding of the role of Pericytes in vascular biology.
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Role of Pericytes in vascular morphogenesis.
EXS, 2005Co-Authors: Christer Betsholtz, Per Lindblom, Holger GerhardtAbstract:Pericytes are solitary, smooth muscle-like mural cells that invest the wall of microvessels. For a long time, the functional significance of the presence and distribution of Pericytes in the microvasculature was unclear. However, in recent years, the application of experimental genetics to the PDGF-B/PDGFRbeta signaling pathway in mice has provided a range of mutants with primary defects in Pericytes, allowing for studies of the physiological consequences of pericyte deficiency in developmental angiogenesis and adult physiology. Interestingly, some of the phenotypic consequences of these mutations resemble human diseases, such as diabetic retinopathy. The studies have also led to the discovery of critical mechanisms involved in pericyte recruitment and differentiation. The present review focuses on genetic data suggesting that Pericytes take active part in developmental angiogenic processes.
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endothelial and nonendothelial sources of pdgf b regulate pericyte recruitment and influence vascular pattern formation in tumors
Journal of Clinical Investigation, 2003Co-Authors: Alexandra Abramsson, Per Lindblom, Christer BetsholtzAbstract:Tumor-infiltrating blood vessels deviate morphologically and biochemically from normal vessels, raising the prospect of selective pharmacological targeting. Current antiangiogenic approaches focus mainly on endothelial cells, but recent data imply that targeting Pericytes may provide additional benefits. Further development of these concepts will require deeper insight into mechanisms of pericyte recruitment and function in tumors. Here, we applied genetic tools to decipher the function of PDGF-B and PDGF-Rβ in pericyte recruitment in a mouse fibrosarcoma model. In tumors transplanted into PDGF-B retention motif–deficient (pdgf-bret/ret) mice, Pericytes were fewer and were partially detached from the vessel wall, coinciding with increased tumor vessel diameter and hemorrhaging. Transgenic PDGF-B expression in tumor cells was able to increase the pericyte density in both WT and pdgf-bret/ret mice but failed to correct the pericyte detachment in pdgf-bret/ret mice. Coinjection of exogenous Pericytes and tumor cells showed that Pericytes require PDGF-Rβ for recruitment to tumor vessels, whereas endothelial PDGF-B retention is indispensable for proper integration of Pericytes in the vessel wall. Our data support the notion that Pericytes serve an important function in tumor vessels and highlight PDGF-B and PDGF-Rβ as promising molecular targets for therapeutic intervention.
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Endothelial-pericyte interactions in angiogenesis
Cell and Tissue Research, 2003Co-Authors: Holger Gerhardt, Christer BetsholtzAbstract:It takes two to make blood vessels—endothelial cells and Pericytes. While the endothelial cells are the better characterized of the two, Pericytes are now coming into focus as important regulators of angiogenesis and blood vessel function, and as potential drug targets. However, Pericytes are still surrounded by much controversy. They are difficult to define, they constitute a heterogeneous population of cells, and their ontogeny is not well understood. They are plastic and have the capacity to differentiate into other mesenchymal cell types, such as smooth muscle cells, fibroblasts and osteoblasts. Recent interest in Pericytes also stems from their potential involvement in diseases such as diabetic microangiopathy, tissue fibrosis, cancer, atherosclerosis and Alzheimer's disease. The present review focuses on the role of Pericytes in physiological angiogenesis. The currently favored view states that the initial endothelial tubes form without pericyte contact, and that subsequent acquisition of pericyte coverage leads to vessel remodeling, maturation and stabilization. Improved means of identifying and visualizing Pericytes now challenge this view and show that high numbers of Pericytes invest in actively sprouting and remodeling vessels. Genetic data demonstrate the critical importance of Pericytes for vascular morphogenesis and function, and imply specific roles for the cell type in various aspects of angiogenesis.
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transcription profiling of platelet derived growth factor b deficient mouse embryos identifies rgs5 as a novel marker for Pericytes and vascular smooth muscle cells
American Journal of Pathology, 2003Co-Authors: Cecilia Bondjers, Mattias Kalen, Mats Hellstrom, Stefan J Scheidl, Alexandra Abramsson, Oliver Renner, Per Lindahl, Hyeseon Cho, John H Kehrl, Christer BetsholtzAbstract:All blood capillaries consist of endothelial tubes surrounded by mural cells referred to as Pericytes. The origin, recruitment, and function of the Pericytes is poorly understood, but the importance of these cells is underscored by the severe cardiovascular defects in mice genetically devoid of factors regulating pericyte recruitment to embryonic vessels, and by the association between pericyte loss and microangiopathy in diabetes mellitus. A general problem in the study of Pericytes is the shortage of markers for these cells. To identify new markers for Pericytes, we have taken advantage of the platelet-derived growth factor (PDGF)-B knockout mouse model, in which developing blood vessels in the central nervous system are almost completely devoid of Pericytes. Using cDNA microarrays, we analyzed the gene expression in PDGF-B null embryos in comparison with corresponding wild-type embryos and searched for down-regulated genes. The most down-regulated gene present on our microarray was RGS5, a member of the RGS family of GTPase-activating proteins for G proteins. In situ hybridization identified RGS5 expression in brain Pericytes, and in Pericytes and vascular smooth muscle cells in certain other, but not all, locations. Absence of RGS5 expression in PDGF-B and PDGFRβ-null embryos correlated with pericyte loss in these mice. Residual RGS5 expression in rare Pericytes suggested that RGS5 is a pericyte marker expressed independently of PDGF-B/Rβ signaling. With RGS5 as a proof-of-principle, our data demonstrate the usefulness of microarray analysis of mouse models for abnormal pericyte development in the identification of new pericyte-specific markers.
Claire M Peppiattwildman - One of the best experts on this subject based on the ideXlab platform.
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supplementary material for an intact kidney slice model to investigate vasa recta properties and function in situ
2017Co-Authors: C Crawford, C Sprott, L Sawbridge, T M Kennedylydon, R J Unwin, Scott S P Wildman, Jgl Munday, Tejal A Desai, Claire M PeppiattwildmanAbstract:Background: Medullary blood flow is via vasa recta capillaries, which possess contractile Pericytes. In vitro studies using isolated descending vasa recta show that Pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E 2 ) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L -NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of Pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow.
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an intact kidney slice model to investigate vasa recta properties and function in situ
Nephron Physiology, 2012Co-Authors: C Crawford, C Sprott, L Sawbridge, T M Kennedylydon, R J Unwin, Scott S P Wildman, Jgl Munday, Tejal A Desai, Claire M PeppiattwildmanAbstract:Background: Medullary blood flow is via vasa recta capillaries, which possess contractile Pericytes. In vitro studies using isolated descending vasa recta show that Pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of Pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow.
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extracellular nucleotides affect pericyte mediated regulation of rat in situ vasa recta diameter
Acta Physiologica, 2011Co-Authors: C Crawford, C Sprott, L Sawbridge, T M Kennedylydon, H Callaghan, Robert J Unwin, R L Simmons, Scott S P Wildman, Harriet M. Syme, Claire M PeppiattwildmanAbstract:AIM We hypothesized that extracellular nucleotides, established as being released from renal tubular epithelial cells, act at Pericytes to regulate vasa recta capillary diameter. METHODS A rat live kidney slice model and video imaging techniques were used to investigate the effects of extracellular nucleotides on in situ (subsurface) vasa recta diameter at pericyte and non-pericyte sites. In addition, RT-qPCR was used to quantify P2 receptor mRNA expression in isolated vasa recta. RESULTS Extracellular ATP, UTP, benzylbenzyl ATP (BzATP) or 2-methylthioATP (2meSATP) evoked a significantly greater vasoconstriction of subsurface vasa recta at Pericytes than at non-pericyte sites. The rank order of agonist potency was BzATP = 2meSATP > ATP = UTP. The vasoconstriction evoked at pericyte sites by ATP was significantly attenuated by the P2 receptor antagonists suramin, pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) (PPADS) or Reactive Blue-2 (RB-2). UTP-evoked vasoconstriction at Pericytes was attenuated by suramin or RB-2 but not PPADS. Interestingly, suramin or PPADS, when applied in the absence of a P2 receptor agonist, evoked a weak but significant vasoconstriction of vasa recta at pericyte sites, suggesting tonic vasodilation by nucleotides. Significant levels of P2X(1, 3 and 7) and P2Y(4 and 6) receptor mRNA were detected in vasa recta. CONCLUSION Extracellular nucleotides act at Pericytes to cause vasoconstriction of in situ vasa recta. Pharmacological characterization, supported by RT-qPCR data, suggests that P2X(1 and 7) and P2Y(4) receptors mediate nucleotide-evoked vasoconstriction of vasa recta by Pericytes. We propose that nucleotides released from renal tubular epithelial cells, in close proximity to vasa recta capillaries, are key in regulating renal medullary blood flow.
C Crawford - One of the best experts on this subject based on the ideXlab platform.
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supplementary material for an intact kidney slice model to investigate vasa recta properties and function in situ
2017Co-Authors: C Crawford, C Sprott, L Sawbridge, T M Kennedylydon, R J Unwin, Scott S P Wildman, Jgl Munday, Tejal A Desai, Claire M PeppiattwildmanAbstract:Background: Medullary blood flow is via vasa recta capillaries, which possess contractile Pericytes. In vitro studies using isolated descending vasa recta show that Pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E 2 ) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L -NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of Pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow.
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an intact kidney slice model to investigate vasa recta properties and function in situ
Nephron Physiology, 2012Co-Authors: C Crawford, C Sprott, L Sawbridge, T M Kennedylydon, R J Unwin, Scott S P Wildman, Jgl Munday, Tejal A Desai, Claire M PeppiattwildmanAbstract:Background: Medullary blood flow is via vasa recta capillaries, which possess contractile Pericytes. In vitro studies using isolated descending vasa recta show that Pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of Pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow.
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extracellular nucleotides affect pericyte mediated regulation of rat in situ vasa recta diameter
Acta Physiologica, 2011Co-Authors: C Crawford, C Sprott, L Sawbridge, T M Kennedylydon, H Callaghan, Robert J Unwin, R L Simmons, Scott S P Wildman, Harriet M. Syme, Claire M PeppiattwildmanAbstract:AIM We hypothesized that extracellular nucleotides, established as being released from renal tubular epithelial cells, act at Pericytes to regulate vasa recta capillary diameter. METHODS A rat live kidney slice model and video imaging techniques were used to investigate the effects of extracellular nucleotides on in situ (subsurface) vasa recta diameter at pericyte and non-pericyte sites. In addition, RT-qPCR was used to quantify P2 receptor mRNA expression in isolated vasa recta. RESULTS Extracellular ATP, UTP, benzylbenzyl ATP (BzATP) or 2-methylthioATP (2meSATP) evoked a significantly greater vasoconstriction of subsurface vasa recta at Pericytes than at non-pericyte sites. The rank order of agonist potency was BzATP = 2meSATP > ATP = UTP. The vasoconstriction evoked at pericyte sites by ATP was significantly attenuated by the P2 receptor antagonists suramin, pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid) (PPADS) or Reactive Blue-2 (RB-2). UTP-evoked vasoconstriction at Pericytes was attenuated by suramin or RB-2 but not PPADS. Interestingly, suramin or PPADS, when applied in the absence of a P2 receptor agonist, evoked a weak but significant vasoconstriction of vasa recta at pericyte sites, suggesting tonic vasodilation by nucleotides. Significant levels of P2X(1, 3 and 7) and P2Y(4 and 6) receptor mRNA were detected in vasa recta. CONCLUSION Extracellular nucleotides act at Pericytes to cause vasoconstriction of in situ vasa recta. Pharmacological characterization, supported by RT-qPCR data, suggests that P2X(1 and 7) and P2Y(4) receptors mediate nucleotide-evoked vasoconstriction of vasa recta by Pericytes. We propose that nucleotides released from renal tubular epithelial cells, in close proximity to vasa recta capillaries, are key in regulating renal medullary blood flow.
Alexander Birbrair - One of the best experts on this subject based on the ideXlab platform.
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Pericyte in Oral Squamous Cell Carcinoma: A Systematic Review
Head and Neck Pathology, 2020Co-Authors: Isabella Bittencourt Valle, Alexander Birbrair, Lauren Frenzel Schuch, Janine Mayra Silva, Alfonso Gala-garcía, Ivana Márcia Alves Diniz, Lucas Guimarães Abreu, Tarcília Aparecida SilvaAbstract:The microenvironment of oral cancer is highly dynamic and has been proved to affect tumor progression. Pericytes are blood vessels surrounding cells that have recently gained attention for their roles in vascular and cancer biology. The objective of the present study was to survey the scientific literature for conclusive evidence about whether Pericytes are part of blood vessels in oral squamous cell carcinoma (OSCC) and their roles in the tumor microenvironment and clinical outcomes. A systematic electronic search was undertaken in Medline Ovid, PubMed, Web of Science, and Scopus. Eligibility criteria were: publications adopting in vivo models of OSCC that included pericyte detection and assessment by pericyte markers (e.g., α-smooth muscle actin, neuron-glial antigen 2 and platelet-derived growth factor receptor-β). The search yielded seven eligible studies (from 2008 to 2018). The markers most commonly used for pericyte detection were α-smooth muscle actin and neuron-glial antigen 2. The studies reviewed showed the presence of immature vessels exhibiting a reduction of pericyte coverage in OSCC and indicated that anti-cancer therapies could contribute to vessel normalization and pericyte regain. The pericyte population is significantly affected during OSCC development and cancer therapy. While these findings might suggest a role for Pericytes in OSCC progression, the limited data available do not allow us to conclude whether they modify the tumor microenvironment and clinical outcome.
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Pericyte Biology: Development, Homeostasis, and Disease.
Advances in experimental medicine and biology, 2018Co-Authors: Alexander BirbrairAbstract:In the nineteenth century, a French researcher, Charles-Marie Benjamin Rouget, revealed a population of contractile cells associated with small blood vessels, which were initially named after him as the Rouget cells. In the twentieth century, a German scientist, Karl Wilhelm Zimmermann, called these cells “Pericytes” due to their anatomical position located in a perivascular position. The word pericyte was derived from “peri” meaning “around” and “cyte” from the word “kytos” (cell), illustrating a cell encircling a blood vessel. Until now, Pericytes are still identified partially based on their specific anatomical location and morphology. Pericytes are present in all vascularized tissues, surrounding blood vessel walls. They encircle endothelial cells and communicate with them along the length of the blood vessels by paracrine signaling and physical contacts. Previously, the accurate distinction of Pericytes from other perivascular cells was difficult, as electron and light microscopy were the sole available techniques capable to image these cells, limiting the information acquired from those works. This resulted in the misleading assumption that Pericytes are merely inert supporting cells, limited exclusively to the physiological function of vascular stability. In the last 10 years, the combination of fluorescent and confocal microscopy with genetic state-of-art techniques, such as fate lineage tracing, enabled remarkable progress in the discovery of multiple novel essential functions for Pericytes in health and disease, before unexpected. Recently, the rapidly expanding understanding of the pathophysiological roles of Pericytes drew the attention of several research groups. Now, we know, for instance, that Pericytes may play immune functions: attract innate leukocytes to exit via sprouting blood vessels, regulate lymphocyte activation, and contribute to the clearance of toxic by-products, having direct phagocytic activity. Pericytes also may behave as stem cells, forming other cell populations, as well as regulate the behavior of other stem cells in their niches. Very little is known about the exact identity of pericyte ancestors within developing tissues, and there is evidence for multiple distinct developmental sources. Pericytes differ in their embryonic origins between tissues and also within the same organ. Importantly, Pericytes from distinct tissues may differ in their distribution, morphology, expression of molecular markers, plasticity, and functions; and, even within the same organ, there are various pericyte subpopulations. This book describes the major contributions of Pericytes to different organ biology in physiological and pathological conditions. Further insights into the biology of Pericytes will have important implications for our understanding of organ development, homeostasis, and disease. This book’s initial title was “Pericyte Biology: Development, Homeostasis, and Disease.” However, due to the current great interest in this topic, we were able to assemble more chapters than would fit in one book, covering pericyte biology under distinct circumstances. Therefore, the book was subdivided into three volumes entitled: “Pericyte Biology: Novel Concepts,” “Pericyte Biology in Different Organs,” and “Pericyte Biology in Disease.” Here, we present a selected collection of detailed chapters on what we know so far about Pericytes. More than 30 chapters written by experts in the field summarize our present knowledge on pericyte biology. Here, we present a selected collection of detailed chapters on what we know so far about Pericytes. More than 30 chapters written by experts in the field summarize our present knowledge on pericyte biology.
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Targeting glioblastoma-derived Pericytes improves chemotherapeutic outcome
Angiogenesis, 2018Co-Authors: Daniel A. P. Guerra, Ana E. Paiva, Isadora F. G. Sena, Patrick O. Azevedo, Walison N. Silva, Akiva Mintz, Alexander BirbrairAbstract:Glioblastoma is the most common malignant brain cancer in adults, with poor prognosis. The blood–brain barrier limits the arrival of several promising anti-glioblastoma drugs, and restricts the design of efficient therapies. Recently, by using state-of-the-art technologies, including thymidine kinase targeting system in combination with glioblastoma xenograft mouse models, it was revealed that targeting glioblastoma-derived Pericytes improves chemotherapy efficiency. Strikingly, ibrutinib treatment enhances chemotherapeutic effectiveness, by targeting Pericytes, improving blood–brain barrier permeability, and prolonging survival. This study identifies glioblastoma-derived pericyte as a novel target in the brain tumor microenvironment during carcinogenesis. Here, we summarize and evaluate recent advances in the understanding of pericyte’s role in the glioblastoma microenvironment.
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Pericyte Plasticity in the Brain
Neuroscience bulletin, 2018Co-Authors: Gabryella S.p. Santos, Akiva Mintz, Luiz Alexandre V. Magno, Marco Aurélio Romano-silva, Alexander BirbrairAbstract:Cerebral Pericytes are perivascular cells that stabilize blood vessels. Little is known about the plasticity of Pericytes in the adult brain in vivo. Recently, using state-of-the-art technologies, including two-photon microscopy in combination with sophisticated Cre/loxP in vivo tracing techniques, a novel role of Pericytes was revealed in vascular remodeling in the adult brain. Strikingly, after pericyte ablation, neighboring Pericytes expand their processes and prevent vascular dilatation. This new knowledge provides insights into pericyte plasticity in the adult brain.
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Pericytes in the Premetastatic Niche
Cancer research, 2018Co-Authors: Ana E. Paiva, Daniel A. P. Guerra, Isadora F. G. Sena, Patrick O. Azevedo, Akiva Mintz, Gabryella S.p. Santos, Luiza Lousado, Julia P. Andreotti, Ricardo Gonçalves, Alexander BirbrairAbstract:The premetastatic niche formed by primary tumor–derived molecules contributes to fixation of cancer metastasis. The design of efficient therapies is limited by the current lack of knowledge about the details of cellular and molecular mechanisms involved in the premetastatic niche formation. Recently, the role of Pericytes in the premetastatic niche formation and lung metastatic tropism was explored by using state-of-the-art techniques, including in vivo lineage-tracing and mice with pericyte-specific KLF4 deletion. Strikingly, genetic inactivation of KLF4 in Pericytes inhibits pulmonary pericyte expansion and decreases metastasis in the lung. Here, we summarize and evaluate recent advances in the understanding of pericyte contribution to premetastatic niche formation. Cancer Res; 78(11); 2779–86. ©2018 AACR .
