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Recruitment and retention: factors that affect pericyte migration

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Abstract

Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte migration and differentiation are complex and have not been fully established. Current literature suggests that platelet-derived growth factor/platelet-derived growth factor receptor-β, sphingosine 1-phosphate/endothelial differentiation gene-1, angiopoietin-1/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, angiopoietin-2/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, transforming growth factor β/activin receptor-like kinase 1, transforming growth factor β/activin receptor-like kinase 5, Semaphorin-3A/Neuropilin, and matrix metalloproteinase activity regulate the recruitment of pericytes to nascent vessels. Interestingly, many of these pathways are directly affected by secreted protein acidic and rich in cysteine (SPARC). Here, we summarize the function of these factors in pericyte migration and discuss if and how SPARC might influence these activities and thus provide an additional layer of control for the recruitment of vascular support cells. Additionally, the consequences of targeted inhibition of pericytes in tumors and the current understanding of pericyte recruitment in pathological environments are discussed.

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References

  1. Armulik A, Genové G, Betsholtz C (2011) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215

    CAS  PubMed  Google Scholar 

  2. Dulauroy S et al (2012) Lineage tracing and genetic ablation of ADAM12(+) perivascular cells identify a major source of profibrotic cells during acute tissue injury. Nat Med 18:1262–1270

    Google Scholar 

  3. Benjamin LE et al (1999) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 103(2):159–165

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Eberhard A et al (2000) Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies. Cancer Res 60(5):1388–1393

    CAS  PubMed  Google Scholar 

  5. Helmlinger G et al (1997) Interstitial pH and pO2 gradients in solid tumors in vivo: high-resolution measurements reveal a lack of correlation. Nat Med 3(2):177–182

    CAS  PubMed  Google Scholar 

  6. Rivera LB, Brekken RA (2011) SPARC promotes pericyte recruitment via inhibition of endoglin-dependent TGF-{beta}1 activity. J Cell Biol 193(7):1305–1319

    CAS  PubMed  Google Scholar 

  7. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    CAS  PubMed  Google Scholar 

  8. Pietras K, Ostman A (2010) Hallmarks of cancer: interactions with the tumor stroma. Exp Cell Res 316(8):1324–1331

    CAS  PubMed  Google Scholar 

  9. Gerhardt H, Semb H (2008) Pericytes: gatekeepers in tumour cell metastasis? J Mol Med 86(2):135–144

    PubMed  Google Scholar 

  10. Song S et al (2005) PDGFRbeta+ perivascular progenitor cells in tumours regulate pericyte differentiation and vascular survival. Nat Cell Biol 7(9):870–879

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Raza A, Franklin MJ, Dudek AZ (2010) Pericytes and vessel maturation during tumor angiogenesis and metastasis. Am J Hematol 85(8):593–598

    CAS  PubMed  Google Scholar 

  12. Chantrain C et al (2006) Mechanisms of pericyte recruitment in tumour angiogenesis: a new role for metalloproteinases. Eur J Cancer 42(3):310–318

    CAS  PubMed  Google Scholar 

  13. Kutcher ME, Herman IM (2009) The pericyte: cellular regulator of microvascular blood flow. Microvasc Res 77(3):235–246

    CAS  PubMed Central  PubMed  Google Scholar 

  14. McCarty MF et al (2007) Overexpression of PDGF-BB decreases colorectal and pancreatic cancer growth by increasing tumor pericyte content. J Clin Investig 117(8):2114–2122

    CAS  PubMed  Google Scholar 

  15. Armulik A (2005) Endothelial/pericyte interactions. Circ Res 97(6):512–523

    CAS  PubMed  Google Scholar 

  16. Sims DE (1986) The pericyte–a review. Tissue Cell 18(2):153–174

    CAS  PubMed  Google Scholar 

  17. Morikawa S et al (2002) Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160(3):985–1000

    PubMed  Google Scholar 

  18. Nehls V, Denzer K, Drenckhahn D (1992) Pericyte involvement in capillary sprouting during angiogenesis in situ. Cell Tissue Res 270(3):469–474

    CAS  PubMed  Google Scholar 

  19. Xian X et al (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116(3):642–651

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Greenberg JI et al (2008) A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature 456(7223):809–813

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Abramsson A (2003) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Investig 112(8):1142–1151

    CAS  PubMed  Google Scholar 

  22. Hashizume H et al (2000) Openings between defective endothelial cells explain tumor vessel leakiness. Am J Pathol 156(4):1363–1380

    CAS  PubMed  Google Scholar 

  23. Nagy JA, Dvorak AM, Dvorak HF (2012) Vascular hyperpermeability, angiogenesis, and stroma generation. Cold Spring Harb Perspect Med 2(2):a006544

    PubMed  Google Scholar 

  24. Amselgruber WM, Schafer M, Sinowatz F (1999) Angiogenesis in the bovine corpus luteum: an immunocytochemical and ultrastructural study. Anat Histol Embryol 28(3):157–166

    CAS  PubMed  Google Scholar 

  25. Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4(11):839–849

    CAS  PubMed  Google Scholar 

  26. Gordon MS, Mendelson DS, Kato G (2010) Tumor angiogenesis and novel antiangiogenic strategies. Int J Cancer 126(8):1777–1787

    CAS  PubMed  Google Scholar 

  27. Eilken HM, Adams RH (2010) Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 22(5):617–625

    CAS  PubMed  Google Scholar 

  28. Fan F et al (2012) Targeting the tumor microenvironment: focus on angiogenesis. J Oncol 2012:281261

    PubMed Central  PubMed  Google Scholar 

  29. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9(6):685–693

    CAS  PubMed  Google Scholar 

  30. Bradshaw AD (2009) The role of SPARC in extracellular matrix assembly. J Cell Commun Signal 3(3–4):239–246

    PubMed Central  PubMed  Google Scholar 

  31. Rivera LB, Bradshaw AD, Brekken RA (2011) The regulatory function of SPARC in vascular biology. Cell Mol Life Sci 68(19):3165–3173

    CAS  PubMed  Google Scholar 

  32. Fredriksson L, Li H, Eriksson U (2004) The PDGF family: four gene products form five dimeric isoforms. Cytokine Growth Factor Rev 15(4):197–204

    CAS  PubMed  Google Scholar 

  33. Homsi J, Daud AI (2007) Spectrum of activity and mechanism of action of VEGF/PDGF inhibitors. Cancer Control 14(3):285–294

    PubMed  Google Scholar 

  34. Wang D et al (1999) Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res 59(7):1464–1472

    CAS  PubMed  Google Scholar 

  35. Hellstrom M et al (1999) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel formation in the mouse. Development 126(14):3047–3055

    CAS  PubMed  Google Scholar 

  36. Lindahl P et al (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277(5323):242–245

    CAS  PubMed  Google Scholar 

  37. Spiegel S, Milstien S (2003) Sphingosine-1-phosphate: an enigmatic signalling lipid. Nat Rev Mol Cell Biol 4(5):397–407

    CAS  PubMed  Google Scholar 

  38. Tamama K et al (2001) Extracellular mechanism through the Edg family of receptors might be responsible for sphingosine-1-phosphate-induced regulation of DNA synthesis and migration of rat aortic smooth-muscle cells. Biochem J 353(Pt 1):139–146

    CAS  PubMed  Google Scholar 

  39. Kluk MJ, Hla T (2001) Role of the sphingosine 1-phosphate receptor EDG-1 in vascular smooth muscle cell proliferation and migration. Circ Res 89(6):496–502

    CAS  PubMed  Google Scholar 

  40. Bornfeldt KE et al (1995) Sphingosine-1-phosphate inhibits PDGF-induced chemotaxis of human arterial smooth muscle cells: spatial and temporal modulation of PDGF chemotactic signal transduction. J Cell Biol 130(1):193–206

    CAS  PubMed  Google Scholar 

  41. Rosenfeldt HM et al (2003) Sphingosine-1-phosphate stimulates contraction of human airway smooth muscle cells. FASEB J 17(13):1789–1799

    CAS  PubMed  Google Scholar 

  42. Boguslawski G et al (2002) Migration of vascular smooth muscle cells induced by sphingosine 1-phosphate and related lipids: potential role in the angiogenic response. Exp Cell Res 274(2):264–274

    CAS  PubMed  Google Scholar 

  43. Sanchez T, Hla T (2004) Structural and functional characteristics of S1P receptors. J Cell Biochem 92(5):913–922

    CAS  PubMed  Google Scholar 

  44. Mizugishi K et al (2005) Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 25(24):11113–11121

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Liu Y et al (2000) Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 106(8):951–961

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Paik JH et al (2004) Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev 18(19):2392–2403

    CAS  PubMed  Google Scholar 

  47. McVerry BJ, Garcia JG (2005) In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal 17(2):131–139

    CAS  PubMed  Google Scholar 

  48. Allende ML, Yamashita T, Proia RL (2003) G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 102(10):3665–3667

    CAS  PubMed  Google Scholar 

  49. Ryu Y et al (2002) Sphingosine-1-phosphate, a platelet-derived lysophospholipid mediator, negatively regulates cellular Rac activity and cell migration in vascular smooth muscle cells. Circ Res 90(3):325–332

    CAS  PubMed  Google Scholar 

  50. Osada M et al (2002) Enhancement of sphingosine 1-phosphate-induced migration of vascular endothelial cells and smooth muscle cells by an EDG-5 antagonist. Biochem Biophys Res Commun 299(3):483–487

    CAS  PubMed  Google Scholar 

  51. Loughna S, Sato TN (2001) Angiopoietin and Tie signaling pathways in vascular development. Matrix Biol 20(5–6):319–325

    CAS  PubMed  Google Scholar 

  52. Vontell D, Armulik A, Betsholtz C (2006) Pericytes and vascular stability. Exp Cell Res 312(5):623–629

    CAS  Google Scholar 

  53. Deroanne CF et al (1997) Angiogenesis by fibroblast growth factor 4 is mediated through an autocrine up-regulation of vascular endothelial growth factor expression. Cancer Res 57(24):5590–5597

    CAS  PubMed  Google Scholar 

  54. Lamalice L, Le Boeuf F, Huot J (2007) Endothelial cell migration during angiogenesis. Circ Res 100(6):782–794

    CAS  PubMed  Google Scholar 

  55. Fiedler U et al (2006) Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med 12(2):235–239

    CAS  PubMed  Google Scholar 

  56. Nasarre P et al (2009) Host-derived angiopoietin-2 affects early stages of tumor development and vessel maturation but is dispensable for later stages of tumor growth. Cancer Res 69(4):1324–1333

    CAS  PubMed Central  PubMed  Google Scholar 

  57. Falcon BL et al (2009) Contrasting actions of selective inhibitors of angiopoietin-1 and angiopoietin-2 on the normalization of tumor blood vessels. Am J Pathol 175(5):2159–2170

    CAS  PubMed  Google Scholar 

  58. Imanishi Y et al (2007) Angiopoietin-2 stimulates breast cancer metastasis through the alpha(5)beta(1) integrin-mediated pathway. Cancer Res 67(9):4254–4263

    CAS  PubMed Central  PubMed  Google Scholar 

  59. Gu C, Giraudo E (2013) The role of semaphorins and their receptors in vascular development and cancer. Exp Cell Res 319(9):1306–1316

    CAS  PubMed  Google Scholar 

  60. Negishi M, Oinuma I, Katoh H (2005) Plexins: axon guidance and signal transduction. Cell Mol Life Sci 62(12):1363–1371

    CAS  PubMed  Google Scholar 

  61. Serini G et al (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424(6947):391–397

    CAS  PubMed  Google Scholar 

  62. Chakraborty G et al (2012) Semaphorin 3A suppresses tumor growth and metastasis in mice melanoma model. PLoS ONE 7(3):e33633

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Maione F et al (2009) Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest 119(11):3356–3372

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Banu N et al (2006) Semaphorin 3C regulates endothelial cell function by increasing integrin activity. FASEB J 20(12):2150–2152

    CAS  PubMed  Google Scholar 

  65. Nelson AR et al (2000) Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol 18(5):1135–1149

    CAS  PubMed  Google Scholar 

  66. Chang C, Werb Z (2001) The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol 11(11):S37–S43

    CAS  PubMed Central  PubMed  Google Scholar 

  67. McCawley LJ, Matrisian LM (2001) Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol 13(5):534–540

    CAS  PubMed  Google Scholar 

  68. Stetler-Stevenson WG, Liotta LA, Kleiner DE Jr (1993) Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7(15):1434–1441

    CAS  PubMed  Google Scholar 

  69. Kim J et al (1998) Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Cell 94(3):353–362

    CAS  PubMed  Google Scholar 

  70. Himelstein BP et al (1994) Metalloproteinases in tumor progression: the contribution of MMP-9. Invasion Metastasis 14(1–6):246–258

    CAS  PubMed  Google Scholar 

  71. Coussens LM et al (2000) MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell 103(3):481–490

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Basset P et al (1997) Matrix metalloproteinases as stromal effectors of human carcinoma progression: therapeutic implications. Matrix Biol 15(8–9):535–541

    CAS  PubMed  Google Scholar 

  73. Himelstein BP, Muschel RJ (1996) Induction of matrix metalloproteinase 9 expression in breast carcinoma cells by a soluble factor from fibroblasts. Clin Exp Metastasis 14(3):197–208

    CAS  PubMed  Google Scholar 

  74. Guo H et al (1997) Stimulation of matrix metalloproteinase production by recombinant extracellular matrix metalloproteinase inducer from transfected Chinese hamster ovary cells. J Biol Chem 272(1):24–27

    CAS  PubMed  Google Scholar 

  75. Bergers G et al (2000) Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol 2(10):737–744

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Nielsen BS et al (1997) Expression of matrix metalloprotease-9 in vascular pericytes in human breast cancer. Lab Invest 77(4):345–355

    CAS  PubMed  Google Scholar 

  77. Forsyth PA et al (1999) Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer 79(11–12):1828–1835

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Chantrain CF (2004) Stromal matrix metalloproteinase-9 regulates the vascular architecture in neuroblastoma by promoting pericyte recruitment. Cancer Res 64(5):1675–1686

    CAS  PubMed  Google Scholar 

  79. Spurbeck WW et al (2002) Enforced expression of tissue inhibitor of matrix metalloproteinase-3 affects functional capillary morphogenesis and inhibits tumor growth in a murine tumor model. Blood 100(9):3361–3368

    CAS  PubMed  Google Scholar 

  80. Lehti K et al (2005) An MT1-MMP-PDGF receptor-beta axis regulates mural cell investment of the microvasculature. Genes Dev 19(8):979–991

    CAS  PubMed  Google Scholar 

  81. Girolamo F et al (2004) Involvement of metalloprotease-2 in the development of human brain microvessels. Histochem Cell Biol 122(3):261–270

    CAS  PubMed  Google Scholar 

  82. Wang H, Keiser JA (1998) Vascular endothelial growth factor upregulates the expression of matrix metalloproteinases in vascular smooth muscle cells: role of flt-1. Circ Res 83(8):832–840

    CAS  PubMed  Google Scholar 

  83. Cho A, Reidy MA (2002) Matrix metalloproteinase-9 is necessary for the regulation of smooth muscle cell replication and migration after arterial injury. Circ Res 91(9):845–851

    CAS  PubMed  Google Scholar 

  84. Annes JP et al (2004) Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1. J Cell Biol 165(5):723–734

    CAS  PubMed  Google Scholar 

  85. Derynck R et al (1986) The murine transforming growth factor-beta precursor. J Biol Chem 261(10):4377–4379

    CAS  PubMed  Google Scholar 

  86. Munger JS et al (1999) The integrin alpha v beta 6 binds and activates latent TGF beta 1: a mechanism for regulating pulmonary inflammation and fibrosis. Cell 96(3):319–328

    CAS  PubMed  Google Scholar 

  87. Schmierer B, Hill CS (2007) TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility. Nat Rev Mol Cell Biol 8(12):970–982

    CAS  PubMed  Google Scholar 

  88. Imai K et al (1997) Degradation of decorin by matrix metalloproteinases: identification of the cleavage sites, kinetic analyses and transforming growth factor-beta1 release. Biochem J 322(Pt 3):809–814

    CAS  PubMed  Google Scholar 

  89. Lyons RM, Keski-Oja J, Moses HL (1988) Proteolytic activation of latent transforming growth factor-beta from fibroblast-conditioned medium. J Cell Biol 106(5):1659–1665

    CAS  PubMed  Google Scholar 

  90. Saharinen J et al (1999) Latent transforming growth factor-beta binding proteins (LTBPs)–structural extracellular matrix proteins for targeting TGF-beta action. Cytokine Growth Factor Rev 10(2):99–117

    CAS  PubMed  Google Scholar 

  91. Lebrin F et al (2005) TGF-beta receptor function in the endothelium. Cardiovasc Res 65(3):599–608

    CAS  PubMed  Google Scholar 

  92. Sieczkiewicz GJ, Herman IM (2003) TGF-beta 1 signaling controls retinal pericyte contractile protein expression. Microvasc Res 66(3):190–196

    CAS  PubMed  Google Scholar 

  93. Van Geest RJ et al (2010) Differential TGF-{beta} signaling in retinal vascular cells: a role in diabetic retinopathy? Invest Ophthalmol Vis Sci 51(4):1857–1865

    PubMed  Google Scholar 

  94. Kojima S, Harpel PC, Rifkin DB (1991) Lipoprotein (a) inhibits the generation of transforming growth factor beta: an endogenous inhibitor of smooth muscle cell migration. J Cell Biol 113(6):1439–1445

    CAS  PubMed  Google Scholar 

  95. Owens GK (1995) Regulation of differentiation of vascular smooth muscle cells. Physiol Rev 75(3):487–517

    CAS  PubMed  Google Scholar 

  96. Sato Y, Rifkin DB (1989) Inhibition of endothelial cell movement by pericytes and smooth muscle cells: activation of a latent transforming growth factor-beta 1-like molecule by plasmin during co-culture. J Cell Biol 109(1):309–315

    CAS  PubMed  Google Scholar 

  97. Gaengel K et al (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29(5):630–638

    CAS  PubMed  Google Scholar 

  98. Puolakkainen PA et al (2004) Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol Cancer Res 2(4):215–224

    CAS  PubMed  Google Scholar 

  99. Arnold SA et al (2010) Lack of host SPARC enhances vascular function and tumor spread in an orthotopic murine model of pancreatic carcinoma. Dis Model Mech 3(1–2):57–72

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Chlenski A et al (2007) SPARC enhances tumor stroma formation and prevents fibroblast activation. Oncogene 26(31):4513–4522

    CAS  PubMed  Google Scholar 

  101. Arnold S et al (2008) Forced expression of MMP9 rescues the loss of angiogenesis and abrogates metastasis of pancreatic tumors triggered by the absence of host SPARC. Exp Biol Med (Maywood) 233(7):860–873

    CAS  Google Scholar 

  102. Motamed K et al (2002) Inhibition of PDGF-stimulated and matrix-mediated proliferation of human vascular smooth muscle cells by SPARC is independent of changes in cell shape or cyclin-dependent kinase inhibitors. J Cell Biochem 84(4):759–771

    PubMed  Google Scholar 

  103. Raines EW et al (1992) The extracellular glycoprotein SPARC interacts with platelet-derived growth factor (PDGF)-AB and -BB and inhibits the binding of PDGF to its receptors. Proc Natl Acad Sci USA 89(4):1281–1285

    CAS  PubMed  Google Scholar 

  104. Dore-Duffy P et al (2000) Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res 60(1):55–69

    CAS  PubMed  Google Scholar 

  105. Duz B et al (2007) The effect of moderate hypothermia in acute ischemic stroke on pericyte migration: an ultrastructural study. Cryobiology 55(3):279–284

    PubMed  Google Scholar 

  106. Claudio L, Brosnan CF (1992) Effects of prazosin on the blood-brain barrier during experimental autoimmune encephalomyelitis. Brain Res 594(2):233–243

    CAS  PubMed  Google Scholar 

  107. Kunz J et al (1995) Changes in the expression pattern of blood-brain barrier-associated pericytic aminopeptidase N (pAP N) in the course of acute experimental autoimmune encephalomyelitis. J Neuroimmunol 59(1–2):41–55

    CAS  PubMed  Google Scholar 

  108. Dore-Duffy P et al (1996) Recovery phase of acute experimental autoimmune encephalomyelitis in rats corresponds to development of endothelial cell unresponsiveness to interferon gamma activation. J Neurosci Res 44(3):223–234

    CAS  PubMed  Google Scholar 

  109. Bolton C (1997) Neurovascular damage in experimental allergic encephalomyelitis: a target for pharmacological control. Mediat Inflamm 6(5–6):295–302

    CAS  Google Scholar 

  110. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201

    CAS  PubMed  Google Scholar 

  111. Hammes HP et al (2002) Pericytes and the pathogenesis of diabetic retinopathy. Diabetes 51(10):3107–3112

    CAS  PubMed  Google Scholar 

  112. Frank RN, Turczyn TJ, Das A (1990) Pericyte coverage of retinal and cerebral capillaries. Invest Ophthalmol Vis Sci 31(6):999–1007

    CAS  PubMed  Google Scholar 

  113. Feng Y et al (2008) Angiopoietin-2 deficiency decelerates age-dependent vascular changes in the mouse retina. Cell Physiol Biochem 21(1–3):129–136

    CAS  PubMed  Google Scholar 

  114. Kischer CW (1992) The microvessels in hypertrophic scars, keloids and related lesions: a review. J Submicrosc Cytol Pathol 24(2):281–296

    CAS  PubMed  Google Scholar 

  115. Zagzag D et al (2000) Vascular apoptosis and involution in gliomas precede neovascularization: a novel concept for glioma growth and angiogenesis. Lab Invest 80(6):837–849

    CAS  PubMed  Google Scholar 

  116. Machein MR et al (2004) Angiopoietin-1 promotes tumor angiogenesis in a rat glioma model. Am J Pathol 165(5):1557–1570

    CAS  PubMed  Google Scholar 

  117. Vermeulen PB et al (2001) Liver metastases from colorectal adenocarcinomas grow in three patterns with different angiogenesis and desmoplasia. J Pathol 195(3):336–342

    CAS  PubMed  Google Scholar 

  118. Bexell D et al (2009) Bone marrow multipotent mesenchymal stroma cells act as pericyte-like migratory vehicles in experimental gliomas. Mol Ther 17(1):183–190

    CAS  PubMed  Google Scholar 

  119. Li W et al (1996) Cultured retinal capillary pericytes die by apoptosis after an abrupt fluctuation from high to low glucose levels: a comparative study with retinal capillary endothelial cells. Diabetologia 39(5):537–547

    CAS  PubMed  Google Scholar 

  120. Khoury J, Langleben D (1996) Platelet-activating factor stimulates lung pericyte growth in vitro. Am J Physiol 270(2 Pt 1):L298–L304

    CAS  PubMed  Google Scholar 

  121. Zhu M et al (2000) The human hyaloid system: cell death and vascular regression. Exp Eye Res 70(6):767–776

    CAS  PubMed  Google Scholar 

  122. Benjamin LE, Hemo I, Keshet E (1998) A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development 125(9):1591–1598

    CAS  PubMed  Google Scholar 

  123. Gee MS et al (2003) Tumor vessel development and maturation impose limits on the effectiveness of anti-vascular therapy. Am J Pathol 162(1):183–193

    PubMed  Google Scholar 

  124. Pietras K, Hanahan D (2005) A multitargeted, metronomic, and maximum-tolerated dose “chemo-switch” regimen is antiangiogenic, producing objective responses and survival benefit in a mouse model of cancer. J Clin Oncol 23(5):939–952

    CAS  PubMed  Google Scholar 

  125. Bergers G (2003) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Investig 111(9):1287–1295

    CAS  PubMed  Google Scholar 

  126. Erber R et al (2004) Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J 18(2):338–340

    CAS  PubMed  Google Scholar 

  127. Shaheen RM et al (2001) Inhibited growth of colon cancer carcinomatosis by antibodies to vascular endothelial and epidermal growth factor receptors. Br J Cancer 85(4):584–589

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Ozerdem U (2006) Targeting of pericytes diminishes neovascularization and lymphangiogenesis in prostate cancer. Prostate 66(3):294–304

    CAS  PubMed  Google Scholar 

  129. Reinmuth N et al (2001) Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. FASEB J 15(7):1239–1241

    CAS  PubMed  Google Scholar 

  130. Waite JC et al (2011) Dynamic imaging of the effector immune response to listeria infection in vivo. PLoS Pathog 7(3):e1001326

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Proebstl D et al (2012) Pericytes support neutrophil subendothelial cell crawling and breaching of venular walls in vivo. J Exp Med 209(6):1219–1234

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Arjaans M et al (2013) Bevacizumab-induced normalization of blood vessels in tumors hampers antibody uptake. Cancer Res 73:3347–3355

    Google Scholar 

  133. Sorensen AG et al (2012) Increased survival of glioblastoma patients who respond to antiangiogenic therapy with elevated blood perfusion. Cancer Res 72(2):402–407

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Van der Veldt AA et al (2012) Rapid decrease in delivery of chemotherapy to tumors after anti-VEGF therapy: implications for scheduling of anti-angiogenic drugs. Cancer Cell 21(1):82–91

    PubMed  Google Scholar 

  135. Bohndiek SE et al (2012) Hyperpolarized (13)C spectroscopy detects early changes in tumor vasculature and metabolism after VEGF neutralization. Cancer Res 72(4):854–864

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Kutluk Cenik B et al (2013) BIBF 1120 (Nintedanib), a triple angiokinase inhibitor, induces hypoxia but not EMT and blocks progression of preclinical models of lung and pancreatic cancer. Mol Cancer Ther 12(6):992–1001

    Google Scholar 

  137. Walshe TE et al (2009) TGF-beta is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS ONE 4(4):e5149

    PubMed Central  PubMed  Google Scholar 

  138. Itoh F et al (2009) Poor vessel formation in embryos from knock-in mice expressing ALK5 with L45 loop mutation defective in Smad activation. Lab Invest 89(7):800–810

    CAS  PubMed  Google Scholar 

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Acknowledgments

We gratefully acknowledge Drs. Michael Dellinger and Bercin Cenik and other members of the Brekken laboratory for helpful comments on the manuscript, as well as Richard Howdy at Visually Medical for preparation of the illustrations. Supported by The Effie Marie Cain Scholarship in Angiogenesis Research (RAB) and grants from the NIH; R01CA118240 (R.A.B.) and F31 CA168350 (K.Y.A.).

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The authors have no competing interests to disclose.

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Correspondence to Rolf A. Brekken.

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Aguilera, K.Y., Brekken, R.A. Recruitment and retention: factors that affect pericyte migration. Cell. Mol. Life Sci. 71, 299–309 (2014). https://doi.org/10.1007/s00018-013-1432-z

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  • DOI: https://doi.org/10.1007/s00018-013-1432-z

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