Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2013

Open Access 01-12-2013 | Research

TNF-α promotes cerebral pericyte remodeling in vitro, via a switch from α1 to α2 integrins

Authors: Ulrich Tigges, Amin Boroujerdi, Jennifer V Welser-Alves, Richard Milner

Published in: Journal of Neuroinflammation | Issue 1/2013

Login to get access

Abstract

Background

There is increasing evidence to suggest that pericytes play a crucial role in regulating the remodeling state of blood vessels. As cerebral pericytes are embedded within the extracellular matrix (ECM) of the vascular basal lamina, it is important to understand how individual ECM components influence pericyte remodeling behavior, and how cytokines regulate these events.

Methods

The influence of different vascular ECM substrates on cerebral pericyte behavior was examined in assays of cell adhesion, migration, and proliferation. Pericyte expression of integrin receptors was examined by flow cytometry. The influence of cytokines on pericyte functions and integrin expression was also examined, and the role of specific integrins in mediating these effects was defined by function-blocking antibodies. Expression of pericyte integrins within remodeling cerebral blood vessels was analyzed using dual immunofluorescence (IF) of brain sections derived from the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE).

Results

Fibronectin and collagen I promoted pericyte proliferation and migration, but heparan sulfate proteoglycan (HSPG) had an inhibitory influence on pericyte behavior. Flow cytometry showed that cerebral pericytes express high levels of α5 integrin, and lower levels of α1, α2, and α6 integrins. The pro-inflammatory cytokine tumor necrosis factor (TNF)-α strongly promoted pericyte proliferation and migration, and concomitantly induced a switch in pericyte integrins, from α1 to α2 integrin, the opposite to the switch seen when pericytes differentiated. Inhibition studies showed that α2 integrin mediates pericyte adhesion to collagens, and significantly, function blockade of α2 integrin abrogated the pro-modeling influence of TNF-α. Dual-IF on brain tissue with the pericyte marker NG2 showed that while α1 integrin was expressed by pericytes in both stable and remodeling vessels, pericyte expression of α2 integrin was strongly induced in remodeling vessels in EAE brain.

Conclusions

Our results suggest a model in which ECM constituents exert an important influence on pericyte remodeling status. In this model, HSPG restricts pericyte remodeling in stable vessels, but during inflammation, TNF-α triggers a switch in pericyte integrins from α1 to α2, thereby stimulating pericyte proliferation and migration on collagen. These results thus define a fundamental molecular mechanism in which TNF-α stimulates pericyte remodeling in an α2 integrin-dependent manner.
Appendix
Available only for authorised users
Literature
1.
Andreeva ER, Pugach IM, Gordon D, Orekhov AN: Continuous subendothelial network formed by pericyte-like cells in human vascular bed. Tissue Cell 1998, 30:127–135.CrossRefPubMed
2.
Armulik A, Abramsson A, Betsholtz C: Endothelial/pericyte interactions. Circ Res 2005, 97:512–523.CrossRefPubMed
3.
Krueger M, Bechmann I: CNS pericytes: concepts, misconceptions and a way out. Glia 2010, 58:1–10.CrossRefPubMed
4.
5.
Hamilton NB, Attwell D, Hall CN: Pericyte-mediated regulation of capillary diameter: a component of neurovascular coupling in health and disease. Front Neuroenergetics 2010, 2:5.CrossRefPubMedPubMedCentral
6.
7.
Dore-Duffy P, LaManna JC: Physiologic angiodynamics in the brain. Antioxid Redox Signal 2007, 9:1363–1371.CrossRefPubMed
8.
Betsholtz C, Lindholm P, Gerhardt H: Role of pericytes in vascular morphogenesis. EXS 2005, 94:115–125.
9.
Dore-Duffy P, Owen C, Balabnov R, Murphy S, Beaumont T, Rafols JA: Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res 2000, 60:55–69.CrossRefPubMed
10.
Lindahl P, Johansson BR, Leveen P, Betsholtz C: Pericyte loss amd microaneurysm formation in PDGF-B deficient mice. Science 1997, 277:242–245.CrossRefPubMed
11.
Hellstrom M, Kalen M, Lindahl P, Abramsson A, Betsholtz C: Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation. Development 1999, 126:3047–3055.PubMed
12.
Hamann GF, Okada Y, Fitridge R, del Zoppo GJ: Microvascular basal lamina antigens disappear during cerebral ischemia and reperfusion. Stroke 1995, 26:2121–21266.CrossRef
13.
Herken R, Gotz W, Thies M: Appearance of laminin, heparan sulphate proteoglycan and collagen type IV during intital stages of vascularization of the neuroepithelium of the mouse embryo. J Anat 1990, 169:189–195.PubMedPubMedCentral
14.
15.
Li L, Welser JV, Milner R: Absence of the αvβ3 integrin dictates the time-course of angiogenesis in the hypoxic central nervous system: accelerated endothelial proliferation correlates with compensatory increases in α5β1 integrin expression. J Cereb Blood Flow Metab 2010, 30:1031–1043.CrossRefPubMedPubMedCentral
16.
Risau W, Lemmon V: Changes in the vascular extracellular matrix during embryonic vasculogenesis and angiogenesis. Dev Biol 1988, 125:441–450.CrossRefPubMed
17.
Hynes RO: Genetic analyses of cell-matrix interactions in development. Curr Op in Genetics and Development 1994, 4:569–574.CrossRef
18.
Stromblad S, Cheresh DA: Integrins, angiogenesis and vascular cell survival. Chem Biol 1996, 3:881–885.CrossRefPubMed
19.
Hemler ME: Integrins. In Guidebook to the extracellular matrix, anchor and adhesion proteins. Edited by: Kreis T, Vale R. New York: Oxford University Press; 1999:196–212.
20.
21.
Milner R, Hung S, Erokwu B, Dore-Duffy P, LaManna JC, del Zoppo GJ: Increased expression of fibronectin and the α5β1 integrin in angiogenic cerebral blood vessels of mice subject to hypobaric hypoxia. Mol Cell Neurosci 2008, 38:43–52.CrossRefPubMedPubMedCentral
22.
Li L, Liu F, Welser-Alves JV, McCullough LD, Milner R: Upregulation of fibronectin and the α5β1 and αvβ3 integrins on blood vessels within the cerebral ischemic penumbra. Exp Neurol 2012, 233:283–291.CrossRefPubMed
23.
Li L, Welser-Alves JV, van der Flier A, Boroujerdi A, Hynes RO, Milner R: An angiogenic role for the α5β1 integrin in promoting endothelial cell proliferatiion during cerebral hypoxia. Exp Neurol 2012, 237:46–54.CrossRefPubMedPubMedCentral
24.
Milner R, Hung S, Wang X, Berg G, Spatz M, del Zoppo G: Responses of endothelial cell and astrocyte matrix-integrin receptors to ischemia mimic those observed in the neurovascular unit. Stroke 2008, 39:191–197.CrossRefPubMed
25.
26.
Milner R, Campbell IL: The extracellular matrix and cytokines regulate microglial integrin expression and activation. J Immunol 2003, 170:3850–3858.CrossRefPubMed
27.
Welser J, Li L, Milner R: Microglial activation state exerts a biphasic influence on brain endothelial cell proliferation by regulating the balance of TNF and TGF-β1. J Neuroinflammation 2010, 7:89.CrossRefPubMedPubMedCentral
28.
Milner R, Campbell IL: Cytokines regulate microglial adhesion to laminin and astrocyte extracellular matrix via protein kinase C-dependent activation of the α6β1 integrin. J Neurosci 2002, 22:1562–1572.PubMed
29.
Wang J, Milner R: Fibronectin promotes brain capillary endothelial cell survival and proliferation through α5β1 and αvβ3 integrins via MAP kinase signaling. J Neurochem 2006, 96:148–159.CrossRefPubMed
30.
Klein S, Roghani M, Rifkin DB: Fibroblast growth factors as angiogenesis factors. EXS 1997, 79:159–192.PubMed
31.
Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ulrich A: High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 1993, 72:835–846.CrossRefPubMed
32.
Baluk P, Yao LC, Feng J, Romano T, Jung SS, Schreiter JL, Yan L, Shealy DJ, McDonald DM: TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest 2009, 119:2954–2964.PubMedPubMedCentral
33.
Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield U, Heine I, Liotta A, Falanga J, Kehrl JH, Fauci AS: Transforming growth factor type β: rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci 1986, 83:4167–4171.CrossRefPubMedPubMedCentral
34.
Shaw LM, Mercurio AM: Interferon gamma and lipopolysaccharide promote macrophage adherence to basement membrane glycoproteins. J Exp Med 1989, 169:303–308.CrossRefPubMed
35.
Wei J, Shaw LM, Mercurio AM: Integrin signalling in leukocytes: lessons from the α6β1 integrin. J Leukoc Biol 1997, 61:397–407.PubMed
36.
Heino J: The collagen receptor integrins have distinct ligand recognition and signaling functions. Matrix Biol 2000, 19:319–323.CrossRefPubMed
37.
Tulla M, Pentikainen OT, Viitasalo T, Kapyla J, Impola U, Nykvist L, Johnson MS, Heino J: Selective binding of collagen subtypes by integrin alpha 1I, alpha 2I and alpha 10I domains. J Biol Chem 2001, 276:48206–48212.PubMed
38.
Roscoe WA, Welsh ME, Carter DE, Karlik SJ: VEGF and angiogenesis in acute and chronic MOG (35–55) peptide induced EAE. J Neuroimmunol 2009, 209:6–15.CrossRefPubMed
39.
Seabrook TJ, Littlewood-Evans A, Brinkmann V, Pollinger B, Schnell C, Hiestand PC: Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions. J Neuroinflammation 2010, 7:95.CrossRefPubMedPubMedCentral
40.
Dore-Duffy P, Katychev A, Wang X, Van Buren E: CNS microvascular pericytes exhibit multipotential stem cell activity. J Cereb Blood Flow Metab 2006, 26:613–624.CrossRefPubMed
41.
Ozerdem U, Grako KA, Dahlin-Huppe K, Monosov E, Stallcup WB: NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis. Dev Dyn 2001, 222:218–227.CrossRefPubMed
42.
Ozerdem U, Monosov E, Stallcup WB: NG2 proteoglycan expression by pericytes in pathological microvasculature. Microvasc Res 2002, 63:129–134.CrossRefPubMed
43.
Yamagishi S, Yonekura H, Yamamoto Y, Fujimori H, Sakurai S, Tanaka N, Yamamoto H: Vascular endothelial growth factor acts as a pericyte mitogen under hypoxic conditions. Lab Invest 1999, 79:501–509.PubMed
44.
McIntosh LC, Muckersie L, Forrester JV: Retinal capillary endothelial cells prefer different substrates for growth and migration. Tissue Cell 1988, 20:193–209.CrossRefPubMed
45.
George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO: Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 1993, 119:1079–1091.PubMed
46.
Kim S, Bell K, Mousa SA, Varner JA: Regulation of angiogenesis in vivo by ligation of integrin α5β1 with the central cell-binding domain of fibronectin. Am J Pathol 2000, 156:1345–1362.CrossRefPubMedPubMedCentral
47.
Abramovitch R, Dafni H, Neeman M, Nagler A, Pines M: Inhibition of neovascularization and tumor growth and facilitation of wound repair by halofuginone, an inhibitor of collagen type I synthesis. Neoplasia 1999, 1:321–329.CrossRefPubMedPubMedCentral
48.
Jackson CJ, Jenkins KL: Type I collagen fibrils promote rapid vascular tube formation upon contact with the apical side of cultured endothelium. Exp Cell Res 1991, 192:319–323.CrossRefPubMed
49.
Gauer S, Schulze-Lohoff E, Schleicher E, Sterzel RB: Glomerular basement membrane-derived perlecan inhibits mesangial cell adhesion to fibronectin. Eur J Cell Biol 1996, 70:233–242.PubMed
50.
Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N: Macrophage-induced angiogenesis is mediated by tumour necrosis factor -α. Nature 1987, 329:630–632.CrossRefPubMed
51.
Takata F, Dohgu S, Matsumoto J, Takahashi H, Machida T, Wakigawa T, Harada E, Miyaji H, Koga M, Nishioku T: Brain pericytes among cells constituting the blood–brain barrier are highly sensitive to tumor necrosis factor-α, releasing matrix metalloproteinase-9 and migrating in vitro. J Neuroinflammation 2011, 8:106.CrossRefPubMedPubMedCentral
52.
Loeser RF, Sadley S, Tan L, Goldring MB: Integrin expression by primary and immortalized human chondrocytes: evidence of a differential role for alpha1 beta1 and alpha2 beta1 integrins in mediating chondrocyte adhesion to types II and VI collagen. Osteoarthritis Cartilage 2000, 8:96–105.CrossRefPubMed
53.
Mendrick DL, Kelly DM: Temporal expression of VLA-2 and modulation of its ligand specificity by rat glomerular epithelial cells in vitro. Lab Invest 1993, 69:690–702.PubMed
54.
Mendrick DL, Kelly DM, DuMont SS, Sandstrom DJ: Glomerular epithelial and mesangial cells differentially modulate the binding specificities of VLA-1 and VLA-2. Lab Invest 1995, 72:367–375.PubMed
55.
Chung CH, Lin KT, Chang CH, Peng HC, Huang TF: The integrin alpha2 beta1 agonist, aggretin, promotes proliferation and migration of VSMC through NF-kB translocation and PDGF production. Br J Pharmacol 2009, 156:846–856.CrossRefPubMedPubMedCentral
56.
Hollenbeck ST, Itoh H, Louie O, Fairies PL, Liu B, Kent KC: Type I collagen synergistically enhances PDGF-induced smooth muscle cell proliferation through pp60src-dependent crosstalk between the alpha2 beta1 integrin and PDGF beta receptor. Biochem Biophys Res Comm 2004, 325:328–337.CrossRefPubMed
57.
Maaser K, Wolf K, Klein CE, Niggemann B, Zanker KS, Brocker EB, Friedl P: Functional hierarchy of simultaneously expressed adhesion receptors: integrin alpha2 beta 1 but not CD44 mediates MV3 melanoma cell migration and matrix reorganization within three-dimensional hylauronan-containing collagen matrices. Mol Biol Cell 1999, 10:3067–3079.CrossRefPubMedPubMedCentral
58.
Lochter A, Navre M, Werb Z, Bissell MJ: Alpha1 and alpha2 integrins mediate invasive activity of mouse mammary carcinoma cells through regulation of stromelysin-1 expression. Mol Biol Cell 1999, 10:271–282.CrossRefPubMedPubMedCentral
59.
van der Bij GJ, Oosterling SJ, Bogels M, Bhoelan F, Flutisma DM, Beelen RH, Meijer S, van Egmond M: Blocking alpha2 integrins on rat CC531s colon carcinoma cells prevents operation-induced augmentation of liver metastases outgrowth. Hepatology 2008, 47:532–543.CrossRefPubMed
60.
Van Slambrouck S, Jenkins AR, Romero AE, Steelant WF: Reorganization of the integrin alpha2 subunit controls cell adhesion and cancer cell invasion in prostate cancer. Int J Oncol 2009, 34:1717–1726.CrossRefPubMedPubMedCentral
61.
Yang C, Zeisberg M, Lively JC, Nyberg P, Afdhal N, Kalluri R: Integrin alpha1 beta1 and alpha2 beta1 are the key regulators of hepatocarcinoma cell invasion across the fibrotic matrix microenvironment. Cancer Res 2003, 63:8312–8317.PubMed
62.
Montesano R, Soulie P, Eble JA, Carrozzino F: Tumour necrosis factor alpha confers an invasive, transformed phenotype on mammary epithelial cells. J Cell Sci 2005, 1118:3487–3500.CrossRef
63.
Sweeney SM, Dilullo G, Slater SJ, Martinez J, Iozzo RV, Lauer-Fields JL, Fields GB: San Antonio JD: Angiogenesis in collagen I requires alpha2 beta1 ligation of a GFP*GER sequence and possibly p38 MAPK activation and focal adhesion disassembly . J Biol Chem 2003, 278:30516–30524.CrossRefPubMed
64.
Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M: VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1 beta1 and alpha2 beta1 integrins. FASEB J 2004, 18:1111–1113.PubMed
65.
Stratman AN, Malotte KM, Mahan RD, Davis MJ, Davis GE: Pericyte recruitment during vasculogenic tube assembly stimulates endothelial basement membrane matrix formation. Blood 2009, 114:5091–5101.CrossRefPubMedPubMedCentral
66.
Chen J, Diacovo TG, Grenache DG, Santoro SA, Zutter MM: The alpha(2) integrin subunit-deficient mouse: a multifaceted phenotype including defects of branching morphogenesis and hemostasis. Am J Pathol 2002, 161:337–344.CrossRefPubMedPubMedCentral
Metadata
Title
TNF-α promotes cerebral pericyte remodeling in vitro, via a switch from α1 to α2 integrins
Authors
Ulrich Tigges
Amin Boroujerdi
Jennifer V Welser-Alves
Richard Milner
Publication date
01-12-2013
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2013
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-10-33

Other articles of this Issue 1/2013

Journal of Neuroinflammation 1/2013 Go to the issue

Research

Human immunodeficiency virus type 1 viral protein R (Vpr) induces CCL5 expression in astrocytes via PI3K and MAPK signaling pathways

Research

HIV infection and drugs of abuse: role of acute phase proteins

Research

Improved neurocognitive functions correlate with reduced inflammatory burden in atrial fibrillation patients treated with intensive cholesterol lowering therapy

Research

Macrophages in inflammatory multiple sclerosis lesions have an intermediate activation status

Research

The growth factor progranulin attenuates neuronal injury induced by cerebral ischemia-reperfusion through the suppression of neutrophil recruitment

Research

Amelioration of autoimmune neuroinflammation by the fusion molecule Fn14·TRAIL