Endothelial-mural cell signaling in vascular development and angiogenesis

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 29, Issue 5, 2009, Pages 630-638

  Gaengel, Konstantin ^a   Genové, Guillem ^a   Armulik, Annika ^a   Betsholtz, Christer ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

Author keywords

Angiopoietin; PDGF; Pericyte; Sphingosine 1 phosphate; TGF

Indexed keywords

ACTIVIN RECEPTOR LIKE KINASE 1; ALPHAVBETA5 INTEGRIN; ALPHAVBETA6 INTEGRIN; ANGIOPOIETIN; ANTINEOPLASTIC AGENT; CONNEXIN 37; ENDOGLIN; FIBRONECTIN; INHIBITOR OF DIFFERENTIATION 2; MYC PROTEIN; NOTCH3 RECEPTOR; PHOSPHOTRANSFERASE INHIBITOR; PLASMINOGEN ACTIVATOR INHIBITOR 1; PLATELET DERIVED GROWTH FACTOR B; PLATELET DERIVED GROWTH FACTOR BETA RECEPTOR; SMAD6 PROTEIN; SMAD7 PROTEIN; SPHINGOSINE 1 PHOSPHATE; SPHINGOSINE KINASE 1; SPHINGOSINE KINASE 2; TIE RECEPTOR; TRANSFORMING GROWTH FACTOR BETA; TRANSFORMING GROWTH FACTOR BETA RECEPTOR 1; TRANSGELIN; VASCULOTROPIN A; VASCULOTROPIN INHIBITOR; VITRONECTIN RECEPTOR; DRUG DERIVATIVE; LYSOPHOSPHOLIPID; NOTCH RECEPTOR; NOTCH3 PROTEIN, HUMAN; SPHINGOSINE; SPHINGOSINE 1-PHOSPHATE;

ANGIOGENESIS; ANTINEOPLASTIC ACTIVITY; BLOOD VESSEL; CADASIL; CANCER THERAPY; CARCINOGENESIS; CELL COMMUNICATION; CELL DENSITY; CELL DIFFERENTIATION; CELL FUNCTION; CELL JUNCTION; CELL MATURATION; CLEAR CELL CARCINOMA; COLORECTAL CARCINOMA; CYTOLOGY; DNA BINDING; DRUG EFFECT; DRUG TARGETING; ENDOTHELIUM CELL; ENZYME PHOSPHORYLATION; GENE MUTATION; GENE TARGETING; HUMAN; IN VIVO STUDY; KIDNEY CARCINOMA; MURAL CELL; NONHUMAN; PANCREAS CANCER; PERICYTE; PHENOTYPE; PRIORITY JOURNAL; PROTEIN EXPRESSION; RECEPTOR UPREGULATION; REVIEW; SIGNAL TRANSDUCTION; STROMA CELL; TARGET CELL; TUMOR CELL; TUMOR GROWTH; TUMOR VASCULARIZATION; VASCULAR SMOOTH MUSCLE; ANIMAL; MOUSE; MOUSE MUTANT; NEOVASCULARIZATION (PATHOLOGY); PATHOPHYSIOLOGY; PHYSIOLOGY;

ADHERENS JUNCTIONS; ANGIOPOIETINS; ANIMALS; LYSOPHOSPHOLIPIDS; MICE; MICE, KNOCKOUT; NEOVASCULARIZATION, PATHOLOGIC; NEOVASCULARIZATION, PHYSIOLOGIC; PERICYTES; RECEPTOR, PLATELET-DERIVED GROWTH FACTOR BETA; RECEPTORS, NOTCH; RECEPTORS, TIE; SIGNAL TRANSDUCTION; SPHINGOSINE;

EID: 65249173169     PISSN: 10795642     EISSN: None     Source Type: Journal    
DOI: 10.1161/ATVBAHA.107.161521     Document Type: Review

References (100)

1. Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97:512-523.
2. Hall AP. Review of the pericyte during angiogenesis and its role in cancer and diabetic retinopathy. Toxicologic Pathology. 2006;34: 763-775.
3. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev. 2008;22:1276-1312.
4. Lindahl P, Johansson BR, Levéen P, Betsholtz C. Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science. 1997; 277:242-245.
5. Hellström M, Kalén 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 in the mouse. Development. 1999;126:3047-3055.
6. Abramsson A, Lindblom P, Betsholtz C. Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors. J Clin Invest. 2003;112:1142-1151.
7. Hirschi KK, Rohovsky SA, Beck LH, Smith SR, D'Amore PA. Endo-thelial cells modulate the proliferation of mural cell precursors via platelet-derived growth factor-BB and heterotypic cell contact. Circ Res. 1999;84:298-305.
8. Bjarnegård M, Enge M, Norlin J, Gustafsdottir S, Fredriksson S, Abramsson A, Takemoto M, Gustafsson E, Fässler R, Betsholtz C. Endothelium-specific ablation of PDGFB leads to pericyte loss and glomerular, cardiac and placental abnormalities. Development. 2004; 131:1847-1857.
9. Lindahl P, Hellström M, Kalén M, Karlsson L, Pekny M, Pekna M, Soriano P, Betsholtz C. Paracrine PDGF-B/PDGF-Rbeta signaling controls mesangial cell development in kidney glomeruli. Development. 1998;125:3313-3322.
10. Ostman A, Andersson M, Betsholtz C, Westermark B, Heldin CH. Identification of a cell retention signal in the B-chain of platelet-derived growth factor and in the long splice version of the A-chain. Cell Regul. 1991;2:503-512.
11. Eming SA, Yarmush ML, Krueger GG, Morgan JR. Regulation of the spatial organization of mesenchymal connective tissue: effects of cell-associated versus released isoforms of platelet-derived growth factor. Am J Pathol. 1999;154:281-289.
12. Lindblom P, Gerhardt H, Liebner S, Abramsson A, Enge M, Hellström M, Backstrom G, Fredriksson S, Landegren U, Nyström HC, Bergström G, Dejana E, Ostman A, Lindahl P, Betsholtz C. Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall. Genes Dev. 2003;17:1835-1840.
13. Abramsson A, Kurup S, Busse M, Yamada S, Lindblom P, Schallmeiner E, Stenzel D, Sauvaget D, Ledin J, Ringvall M, Landegren U, Kjellén L, Bondjers G, Li JP, Lindahl U, Spillmann D, Betsholtz C, Gerhardt H. Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development. Genes Dev. 2007;21:316-331.
14. Saharinen P, Kerkelä K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol. 2005;169:239 -243.
15. Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD. Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell. 1996;87: 1171-1180.
16. Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radz-iejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD. Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science. 1997; 277:55-60.
17. Valenzuela DM, Griffiths JA, Rojas J, Aldrich TH, Jones PF, Zhou H, McClain J, Copeland NG, Gilbert DJ, Jenkins NA, Huang T, Papado-poulos N, Maisonpierre PC, Davis S, Yancopoulos GD. Angiopoietins 3 and 4: diverging gene counterparts in mice and humans. Proc Natl Acad Sci U S A. 1999;96:1904-1909.
18. Dumont DJ, Yamaguchi TP, Conlon RA, Rossant J, Breitman ML. tek, a novel tyrosine kinase gene located on mouse chromosome 4, is expressed in endothelial cells and their presumptive precursors. Oncogene. 1992;7:1471-1480.
19. Wakui S, Yokoo K, Muto T, Suzuki Y, Takahashi H, Furusato M, Hano H, Endou H, Kanai Y. Localization of Ang-1, -2, Tie-2, and VEGF expression at endothelial-pericyte interdigitation in rat angiogenesis. Lab Invest. 2006;86:1172-1184.
20. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L. Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell. 2005;8:211-226.
21. Cai J, Kehoe O, Smith GM, Hykin P, Boulton ME. The angiopoietin/Tie-2 system regulates pericyte survival and recruitment in diabetic retinopathy. Invest Ophthalmol Vis Sci. 2008;49:2163-2171.
22. Korhonen J, Polvi A, Partanen J, Alitalo K. The mouse tie receptor tyrosine kinase gene: expression during embryonic angiogenesis. Oncogene. 1994;9:395-403.
23. Puri MC, Partanen J, Rossant J, Bernstein A. Interaction of the TEK and TIE receptor tyrosine kinases during cardiovascular development. Development. 1999;126:4569-4580.
24. Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD. Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell. 1996;87:1161-1169.
25. Sundberg C, Kowanetz M, Brown LF, Detmar M, Dvorak HF. Stable expression of angiopoietin-1 and other markers by cultured pericytes: phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in vivo. Lab Invest. 2002;82: 387-401.
26. Fiedler U, Reiss Y, Scharpfenecker M, Grunow V, Koidl S, Thurston G, Gale NW, Witzenrath M, Rosseau S, Suttorp N, Sobke A, Herrmann M, Preissner KT, Vajkoczy P, Augustin HG. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006;12:235-239.
27. Dumont DJ, Gradwohl G, Fong GH, Puri MC, Gertsenstein M, Auerbach A, Breitman ML. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev. 1994;8: 1897-1909.
28. Sato TN, Tozawa Y, Deutsch U, Wolburg-Buchholz K, Fujiwara Y, Gendron-Maguire M, Gridley T, Wolburg H, Risau W, Qin Y. Distinct roles of the receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel formation. Nature. 1995;376:70-74.
29. Patan S. TIE1 and TIE2 receptor tyrosine kinases inversely regulate embryonic angiogenesis by the mechanism of intussusceptive micro-vascular growth. Microvasc Res. 1998;56:1-21.
30. Saharinen P, Eklund L, Miettinen J, Wirkkala R, Anisimov A, Wind-erlich M, Nottebaum A, Vestweber D, Deutsch U, Koh GY, Olsen BR, Alitalo K. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol. 2008;10: 527-537.
31. Vikkula M, Boon LM, Carraway KL, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell. 1996;87: 1181-1190.
32. Jones N, Voskas D, Master Z, Sarao R, Jones J, Dumont DJ. Rescue of the early vascular defects in Tek/Tie2 null mice reveals an essential survival function. EMBO Rep. 2001;2:438-445.
33. Puri MC, Rossant J, Alitalo K, Bernstein A, Partanen J. The receptor tyrosine kinase TIE is required for integrity and survival of vascular endothelial cells. EMBO J. 1995;14:5884-5891.
34. Partanen J, Puri MC, Schwartz L, Fischer KD, Bernstein A, Rossant J. Cell autonomous functions of the receptor tyrosine kinase TIE in a late phase of angiogenic capillary growth and endothelial cell survival during murine development. Development. 1996;122:3013-3021.
35. Hammes HP, Lin J, Wagner P, Feng Y, Vom Hagen F, Krzizok T, Renner O, Breier G, Brownlee M, Deutsch U. Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy. Diabetes. 2004;53:1104 -1110.
36. Feng Y, Vom Hagen F, Pfister F, Djokic S, Hoffmann S, Back W, Wagner P, Lin J, Deutsch U, Hammes HP. Impaired pericyte recruitment and abnormal retinal angiogenesis as a result of angiopoietin-2 overexpression. Thromb Haemost. 2007;97:99-108.
37. Feng Y, Pfister F, Schreiter K, Wang Y, Stock O, Vom Hagen F, Wolburg H, Hoffmann S, Deutsch U, Hammes HP. Angiopoietin-2 deficiency decelerates age-dependent vascular changes in the mouse retina. Cell Physiol Biochem. 2008;21:129-136.
38. Allende ML, Proia RL. Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim Biophys Acta. 2002;1582: 222-227.
39. Hla T, Lee MJ, Ancellin N, Liu CH, Thangada S, Thompson BD, Kluk M. Sphingosine-1-phosphate: extracellular mediator or intracellular second messenger? Biochem Pharmacol. 1999;58:201-207.
40. El Bawab S, Roddy P, Qian T, Bielawska A, Lemasters JJ, Hannun YA. Molecular cloning and characterization of a human mitochondrial cer-amidase. J Biol Chem. 2000;275:21508-21513.
41. Kohama T, Olivera A, Edsall L, Nagiec MM, Dickson R, Spiegel S. Molecular cloning and functional characterization of murine sphin-gosine kinase. J Biol Chem. 1998;273:23722-23728.
42. Mandala SM, Thornton R, Tu Z, Kurtz MB, Nickels J, Broach J, Menzeleev R, Spiegel S. Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response. Proc Natl Acad Sci U S A. 1998;95:150-155.
43. Van Veldhoven PP, Mannaerts GP. Sphingosine-phosphate lyase. Adv Lipid Res. 1993;26:69-98.
44. Zhou J, Saba JD. Identification of the first mammalian sphingosine phosphate lyase gene and its functional expression in yeast. Biochem Biophys Res Commun. 1998;242:502-507.
45. Yatomi Y, Igarashi Y, Yang L, Hisano N, Qi R, Asazuma N, Satoh K, Ozaki Y, Kume S. Sphingosine 1-phosphate, a bioactive sphingolipid abundantly stored in platelets, is a normal constituent of human plasma and serum. J Biochem. 1997;121:969-973.
46. Yang L, Yatomi Y, Miura Y, Satoh K, Ozaki Y. Metabolism and functional effects of sphingolipids in blood cells. Br J Haematol. 1999; 107:282-293.
47. Yatomi Y, Ozaki Y, Ohmori T, Igarashi Y. Sphingosine 1-phosphate: synthesis and release. Prostaglandins. 2001;64:107-122.
48. Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL. Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol. 2005;25:11113-11121.
49. Kono M, Mi Y, Liu Y, Sasaki T, Allende ML, Wu YP, Yamashita T, Proia RL. The sphingosine-1-phosphate receptors S1P1, S1P2, and S1P3 function coordinately during embryonic angiogenesis. J Biol Chem. 2004;279:29367-29373.
50. Takuwa Y. Subtype-specific differential regulation of Rho family G proteins and cell migration by the Edg family sphingosine-1-phosphate receptors. Biochim Biophys Acta. 2002;1582:112-120.
51. Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ, Liu CH, Hla T, Spiegel S, Proia RL. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest. 2000;106:951-961.
52. Allende ML, Yamashita T, Proia RL. G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood. 2003;102:3665-3667.
53. Chae SS, Paik JH, Allende ML, Proia RL, Hla T. Regulation of limb development by the sphingosine 1-phosphate receptor S1p1/EDG-1 occurs via the hypoxia/VEGF axis. Dev Biol. 2004;268:441-447.
54. Igarashi J, Erwin PA, Dantas AP, Chen H, Michel T. VEGF induces S1P1 receptors in endothelial cells: Implications for cross-talk between sphingolipid and growth factor receptors. Proc Natl Acad Sci U S A. 2003;100:10664-10669.
55. Lee MJ, Thangada S, Claffey KP, Ancellin N, Liu CH, Kluk M, Volpi M, Sha'afi RI, Hla T. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell. 1999;99:301-312.
56. Paik JH, Skoura A, Chae SS, Cowan AE, Han DK, Proia RL, Hla T. Sphingosine 1-phosphate receptor regulation of N-cadherin mediates vascular stabilization. Genes Dev. 2004;18:2392-2403.
57. McVerry BJ, Garcia JG. In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal. 2005;17:131-139.
58. Goumans MJ, Valdimarsdottir G, Itoh S, Rosendahl A, Sideras P, ten Dijke P. Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors. EMBO J. 2002;21:1743-1753.
59. Ota T, Fujii M, Sugizaki T, Ishii M, Miyazawa K, Aburatani H, Miyazono K. Targets of transcriptional regulation by two distinct type I receptors for transforming growth factor-beta in human umbilical vein endothelial cells. J Cell Physiol. 2002;193:299 -318.
60. Chen S, Kulik M, Lechleider RJ. Smad proteins regulate transcriptional induction of the SM22alpha gene by TGF-beta. Nucleic Acids Res. 2003;31:1302-1310.
61. Oh SP, Seki T, Goss KA, Imamura T, Yi Y, Donahoe PK, Li L, Miyazono K, ten Dijke P, Kim S, Li E. Activin receptor-like kinase 1 modulates transforming growth factor-beta 1 signaling in the regulation of angiogenesis. Proc Natl Acad Sci U S A. 2000;97:2626-2631.
62. Goumans MJ, Valdimarsdottir G, Itoh S, Lebrin F, Larsson J, Mummery C, Karlsson S, ten Dijke P. Activin receptor-like kinase (ALK)1 is an antagonistic mediator of lateral TGFbeta/ALK5 signaling. Mol Cell. 2003;12:817-828.
63. Dickson MC, Martin JS, Cousins FM, Kulkarni AB, Karlsson S, Akhurst RJ. Defective haematopoiesis and vasculogenesis in transforming growth factor-beta 1 knock out mice. Development. 1995;121: 1845-1854.
64. Larsson J, Goumans MJ, Sjöstrand LJ, van Rooijen MA, Ward D, Levéen P, Xu X, ten Dijke P, Mummery CL, Karlsson S. Abnormal angiogenesis but intact hematopoietic potential in TGF-beta type I receptor-deficient mice. EMBO J. 2001;20:1663-1673.
65. Chang H, Huylebroeck D, Verschueren K, Guo Q, Matzuk MM, Zwijsen A. Smad5 knockout mice die at mid-gestation due to multiple embryonic and extraembryonic defects. Development. 1999;126:1631-1642.
66. Yang X, Castilla LH, Xu X, Li C, Gotay J, Weinstein M, Liu PP, Deng CX. Angiogenesis defects and mesenchymal apoptosis in mice lacking SMAD5. Development. 1999;126:1571-1580.
67. Oshima M, Oshima H, Taketo MM. TGF-beta receptor type II deficiency results in defects of yolk sac hematopoiesis and vasculogenesis. Dev Biol. 1996;179:297-302.
68. Seki T, Yun J, Oh SP. Arterial endothelium-specific activin receptor-like kinase 1 expression suggests its role in arterialization and vascular remodeling. Circ Res. 2003;93:682-689.
69. Urness LD, Sorensen LK, Li DY. Arteriovenous malformations in mice lacking activin receptor-like kinase-1. Nat Genet. 2000;26:328 -331.
70. ten Dijke P, Goumans MJ, Pardali E. Endoglin in angiogenesis and vascular diseases. Angiogenesis. 2008;11:79-89.
71. Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP. Defective angiogenesis in mice lacking endoglin. Science. 1999;284:1534-1537.
72. Sorensen LK, Brooke BS, Li DY, Urness LD. Loss of distinct arterial and venous boundaries in mice lacking endoglin, a vascular-specific TGFbeta coreceptor. Dev Biol. 2003;261:235-250.
73. Berg JN, Gallione CJ, Stenzel TT, Johnson DW, Allen WP, Schwartz CE, Jackson CE, Porteous ME, Marchuk DA. The activin receptor-like kinase 1 gene: genomic structure and mutations in hereditary hemor-rhagic telangiectasia type 2. Am J Hum Genet. 1997;61:60-67.
74. McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J. Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1. Nat Genet. 1994;8: 345-351.
75. Seki T, Hong KH, Oh SP. Nonoverlapping expression patterns of ALK1 and ALK5 reveal distinct roles of each receptor in vascular development. Lab Invest. 2006;86:116-129.
76. Carvalho RL, Itoh F, Goumans MJ, Lebrin F, Kato M, Takahashi S, Ema M, Itoh S, van Rooijen M, Bertolino P, ten Dijke P, Mummery CL. Compensatory signalling induced in the yolk sac vasculature by deletion of TGFbeta receptors in mice. J Cell Sci. 2007;120:4269-4277.
77. Carvalho RL, Jonker L, Goumans MJ, Larsson J, Bouwman P, Karlsson S, Dijke PT, Arthur HM, Mummery CL. Defective paracrine signalling by TGFbeta in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia. Development. 2004;131: 6237-6247.
78. Sato Y, Rifkin DB. 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. 1989;109:309-315.
79. Hirschi KK, Burt JM, Hirschi KD, Dai C. Gap junction communication mediates transforming growth factor-beta activation and endothelial-induced mural cell differentiation. Circ Res. 2003;93:429-437.
80. Krüger O, Plum A, Kim JS, Winterhager E, Maxeiner S, Hallas G, Kirchhoff S, Traub O, Lamers WH, Willecke K. Defective vascular development in connexin 45-deficient mice. Development. 2000;127: 4179-4193.
81. Theis M, de Wit C, Schlaeger TM, Eckardt D, Krüger O, Döring B, Risau W, Deutsch U, Pohl U, Willecke K. Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene. Genesis. 2001;29:1-13.
82. Bader BL, Rayburn H, Crowley D, Hynes RO. Extensive vasculo-genesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins. Cell. 1998;95:507-519.
83. Zhu J, Motejlek K, Wang D, Zang K, Schmidt A, Reichardt LF. beta8 integrins are required for vascular morphogenesis in mouse embryos. Development. 2002;129:2891-2903.
84. Cambier S, Gline S, Mu D, Collins R, Araya J, Dolganov G, Einheber S, Boudreau N, Nishimura SL. Integrin alpha(v)beta8-mediated activation of transforming growth factor-beta by perivascular astrocytes: an angiogenic control switch. Am J Pathol. 2005;166:1883-1894.
85. Wipff PJ, Hinz B. Integrins and the activation of latent transforming growth factor beta1 - An intimate relationship. Eur J Cell Biol. 2008; 87:601-615.
86. Joutel A, Corpechot C, Ducros A, Vahedi K, Chabriat H, Mouton P, Alamowitch S, Domenga V, Cécillion M, Marechal E, Maciazek J, Vayssiere C, Cruaud C, Cabanis EA, Ruchoux MM, Weissenbach J, Bach JF, Bousser MG, Tournier-Lasserve E. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature. 1996;383:707-710.
87. Ruchoux MM, Guerouaou D, Vandenhaute B, Pruvo JP, Vermersch P, Leys D. Systemic vascular smooth muscle cell impairment in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoen-cephalopathy. Acta Neuropathol. 1995;89:500-512.
88. Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A. Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev. 2004;18:2730-2735.
89. Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, Campos-Ortega JA, Weinstein BM. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development. 2001;128:3675-3683.
90. Jin S, Hansson EM, Tikka S, Lanner F, Sahlgren C, Farnebo F, Baumann M, Kalimo H, Lendahl U. Notch signaling regulates platelet-derived growth factor receptor-beta expression in vascular smooth muscle cells. Circ Res. 2008;102:1483-1491.
91. Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodelling is defined by pericyte coverage of the preformed endothe- lial network and is regulated by PDGF-B and VEGF. Development. 1998;125:1591-1598.
92. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest. 1999;103:159 -165.
93. Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111:1287-1295.
94. Erber R, Thurnher A, Katsen AD, Groth G, Kerger H, Hammes HP, Menger MD, Ullrich A, Vajkoczy P. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338-340.
95. Hainsworth JD, Spigel DR, Sosman JA, Burris HA, Farley C, Cucullu H, Yost K, Hart LL, Sylvester L, Waterhouse DM, Greco FA. Treatment of advanced renal cell carcinoma with the combination bevacizumab/ erlotinib/imatinib: a phase I/II trial. Clinical Genitourinary Cancer. 2007;5:427-432.
96. Yonenaga Y, Mori A, Onodera H, Yasuda S, Oe H, Fujimoto A, Tachibana T, Imamura M. Absence of smooth muscle actin-positive pericyte coverage of tumor vessels correlates with hematogenous metastasis and prognosis of colorectal cancer patients. Oncology. 2005; 69:159-166.
97. Xian X, Håkansson J, Ståhlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H. Pericytes limit tumor cell metastasis. J Clin Invest. 2006; 116:642-651.
98. Berger M, Bergers G, Arnold B, Hämmerling GJ, Ganss R. Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization. Blood. 2005;105:1094-1101.
99. Nisancioglu MH, Mahoney WM, Kimmel DD, Schwartz SM, Betsholtz C, Genové G. Generation and characterization of rgs5 mutant mice. Mol Cell Biol. 2008;28:2324-2331.
100. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, Rabie T, Kaden S, Gröne HJ, Hämmerling GJ, Arnold B, Ganss R. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453:410-414.