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Abstract

Blood vessels are composed of two interacting cell types. Endothelial cells form the inner lining of the vessel wall, and perivascular cells—referred to as pericytes, vascular smooth muscle cells or mural cells—envelop the surface of the vascular tube. Over the last decades, studies of blood vessels have concentrated mainly on the endothelial cell component, especially when the first angiogenic factors were discovered, while the interest in pericytes has lagged behind. Pericytes are, however, functionally significant; when vessels lose pericytes, they become hemorrhagic and hyperdilated, which leads to conditions such as edema, diabetic retinopathy, and even embryonic lethality. Recently, pericytes have gained new attention as functional and critical contributors to tumor angiogenesis and therefore as potential new targets for antiangiogenic therapies. Pericytes are complex. Their ontogeny is not completely understood, and they perform various functions throughout the body. This review article describes the current knowledge about the nature of pericytes and their functions during vessel growth, vessel maintenance, and pathological angiogenesis.

References

Abbott, N.J. (

2002
) Astrocyte-endothelial interactions and blood-brain barrier permeability.
J. Anat.
200
,
629
-638.

Abramsson, A., Berlin, O., Papayan, H., Paulin, D., Shani, M., and Bets holtz, C. (

2002
) Analysis of mural cell recruitment to tumor vessels.
Circulation
105
,
112
-117.

Abramsson, A., Lindblom, P., and Betsholtz, C. (

2003
) Endothelial and nonendothelial sources of PDGF-B regulate pericyte recruitment and influence vascular pattern formation in tumors.
J. Clin. Invest.
112
,
1142
-1151.

Aiello, L.P., Pierce, E.A., Foley, E.D., Takagi, H., Chen, H., Riddle, L., Fer rara, N., King, G.L., and Smith, L.E. (

1995
) Suppression of retinal neo vascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins.
Proc. Natl. Acad. Sci. USA
92
,
10457
-10461.

Balabanov, R., Washington, R., Wagnerova, J., and Dore-Duffy, P. (

1996
) CNS microvascular pericytes express macrophage-like function, cell surface integrin alpha M, and macrophage marker ED-2.
Microvasc. Res.
52
,
127
-142.

Ballabh, P., Braun, A., and Nedergaard, M. (

2004
) The blood-brain barrier: An overview. Structure, regulation, and clinical implications.
Neurobiol. Dis.
16
,
1
-13.

Benjamin, L.E. (

2001
) Glucose, VEGF-A, and diabetic complications.
Am. J. Pathol.
158
,
1181
-1184.

Benjamin, L.E., Hemo, I., and 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
,
1591
-1598.

Benjamin, L.E., Golijanin, D., Itin, A., Pode, D., and Keshet, E. (

1999
) Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal [see comment].
J. Clin. Invest.
103
,
159
-165.

Berger, M., Bergers, G., Arnold, B., Hammerling, G.J., and Ganss, R. (

2005
) Regulator of G-protein signaling-5 induction in pericytes coincides with active vessel remodeling during neovascularization.
Blood
105
,
1094
-1101.

Bergers, G., and Benjamin, L.E. (

2003
) Tumorigenesis and the angiogenic switch.
Nat. Rev. Cancer
3
,
401
-410.

Bergers, G., Song, S., Meyer-Morse, N., Bergsland, E.B., and Hanahan, D. (

2003
) Benefits of targeting both pericytes and endothelial cells in the tumor vasculature.
J. Clin. Invest.
111
,
1287
-1295

Bergwerff, M., Verberne, M.E., DeRuiter, M.C., Poelmann, R.E., and Gittenberger-de Groot, A. C. (

1998
) Neural crest cell contribution to the developing circulatory system: Implications for vascular morphol ogy?
Circ. Res.
82
,
221
-231.

Betsholtz, C. (

2004
) Insight into the physiological functions of PDGF through genetic studies in mice.
Cytokine Growth Factor Rev.
15
,
215
-228.

Betsholtz, C., Karlsson, L., and Lindahl, P. (

2001
) Developmental roles of platelet-derived growth factors.
Bioessays
23
,
494
-507.

Bondjers, C., Kalen, M., Hellstrom, M., Scheidl, S.J., Abramsson, A., Renner, O., Lindahl, P., Cho, H., Kehrl, J., and Betsholtz, C. (

2003
) Transcription profiling of platelet-derived growth factor-B-deficient mouse embryos identifies RGS5 as a novel marker for pericytes and vascular smooth muscle cells.
Am. J. Pathol.
162
,
721
-729.

Cai, J., and Boulton, M. (

2002
) The pathogenesis of diabetic retinopathy: Old concepts and new questions.
Eye
16
,
242
-260.

Campochiaro, P.A. (

2004
) Ocular neovascularisation and excessive vascular permeability.
Expert Opin. Biol. Ther.
4
,
1395
-1402.

Carmeliet, P. (

2004
) Manipulating angiogenesis in medicine.
J. Intern. Med.
255
,
538
-561.

Chen, S., and Lechleider, R.J. (

2004
) Transforming growth factor-beta-induced differentiation of smooth muscle from a neural crest stem cell line.
Circ. Res.
94
,
1195
-1202.

Cho, H., Kozasa, T., Bondjers, C., Betsholtz, C., and Kehrl, J.H. (

2003
) Pericyte-specific expression of Rgs5: Implications for PDGF and EDG receptor signaling during vascular maturation.
FASEB J.
17
,
440
-442.

Cleaver, O., and Melton, D.A. (

2003
) Endothelial signaling during development.
Nat. Med.
9
,
661
-668.

Creazzo, T.L., Godt, R.E., Leatherbury, L., Conway, S.J., and Kirby, M.L. (

1998
) Role of cardiac neural crest cells in cardiovascular development.
Annu. Rev. Physiol.
60
,
267
-286.

Darland, D.C., and D'Amore, P.A. (

2001
) TGF beta is required for the for mation of capillary-like structures in three-dimensional cocultures of 10T1/2 and endothelial cells.
Angiogenesis
4
,
11
-20.

Ding, R., Darland, D.C., Parmacek, M.S., and D'Amore, P.A. (

2004
) Endothelial-mesenchymal interactions in vitro reveal molecular mecha nisms of smooth muscle/pericyte differentiation.
Stem Cells Dev.
13
,
509
-520.

Enge, M., Bjarnegard, M., Gerhardt, H., Gustafsson, E., Kalen, M., Asker, N., Hammes, H.P., Shani, M., Fassler, R., and Betsholtz, C. (

2002
) Endothelium-specific platelet-derived growth factor-B ablation mimics diabetic retinopathy.
EMBO J.
21
,
4307
-4316.

Etchevers, H.C., Couly, G., and Le Douarin, N.M. (

2002
) Morphogenesis of the branchial vascular sector.
Trends Cardiovasc. Med.
12
,
299
-304.

Folkman, J. (

2000
) Tumor angiogenesis. In: Bast, R.C., Jr., Kufe, D.W., Pollock, R.E., Weichselbaum, R.R., Holland, J.F., and Frei, E., III (Eds.),
Holland Frei Cancer Medicine
. Hamilton, Ontario: B.C. Decker Inc., pp.
9
-152.

Gerhardt, H., and Betsholtz, C. (

2003
) Endothelial-pericyte interactions in angiogenesis.
Cell Tissue Res.
314
,
15
-23.

Gerhardt, H., Golding, M., Fruttiger, M., Ruhrberg, C., Lundkvist, A., Abramsson, A., Jeltsch, M., Mitchell, C., Alitalo, K., Shima, D., and Betsholtz, C. (

2003
) VEGF guides angiogenic sprouting utilizing endo thelial tip cell filopodia.
J. Cell Biol.
161
,
1163
-1177.

Gittenberger-de Groot, A.C., DeRuiter, M.C., Bergwerff, M., and Poelmann, R.E. (

1999
) Smooth muscle cell origin and its relation to hetero geneity in development and disease.
Arterioscler. Thromb. Vasc. Biol.
19
,
1589
-1594.

Guo, P., Hu, B., Gu, W., Xu, L., Wang, D., Huang, H.J., Cavenee, W.K., and Cheng, S.Y. (

2003
) Platelet-derived growth factor-B enhances glioma angiogenesis by stimulating vascular endothelial growth factor expression in tumor endothelia and by promoting pericyte recruitment.
Am. J. Pathol.
162
,
1083
-1093.

Guy, C.T., Webster, M.A., Schaller, M., Parsons, T.J., Cardiff, R.D., and Muller, W.J. (

1992
) Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease.
Proc. Natl. Acad. Sci. USA
89
,
10578
-10582.

Hammes, H.P., Lin, J., Renner, O., Shani, M., Lundqvist, A., Betsholtz, C., Brownlee, M., and Deutsch, U. (

2002
) Pericytes and the pathogenesis of diabetic retinopathy.
Diabetes
51
,
3107
-3112.

Hanahan, D. (

1997
) Signaling vascular morphogenesis and maintenance.
Science
277
,
48
-50.

Hayashi, K., Nakao, S., Nakaoke, R., Nakagawa, S., Kitagawa, N., and Niwa, M. (

2004
) Effects of hypoxia on endothelial/pericytic co-culture model of the blood-brain barrier.
Regul. Pept.
123
,
77
-83.

Hellstrom, M., Kalen, M., Lindahl, P., Abramsson, A., and Betsholtz, C. (

1999
) Role of PDGF-B and PDGFR-beta in recruitment of vascular smooth muscle cells and pericytes during embryonic blood vessel for mation in the mouse.
Development
126
,
3047
-3055.

Hirschi, K.K., and D'Amore, P.A. (

1996
) Pericytes in the microvasculature.
Cardiovasc. Res.
32
,
687
-698.

Hirschi, K.K., Rohovsky, S.A., and D'Amore, P.A. (

1998
) PDGF, TGF-beta, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate.
J. Cell Biol.
141
,
805
-814.

Hirschi, K.K., Rohovsky, S.A., Beck, L.H., Smith, S.R., and D'Amore, P.A. (

1999
) Endothelial cells modulate the proliferation of mural cell precur sors via platelet-derived growth factor-BB and heterotypic cell contact.
Circ. Res.
84
,
298
-305.

Jain, R.K. (

2003
) Molecular regulation of vessel maturation.
Nat. Med.
9
,
685
-693.

Knittel, T., Dinter, C., Kobold, D., Neubauer, K., Mehde, M., Eichhorst, S., and Ramadori, G. (

1999
) Expression and regulation of cell adhesion molecules by hepatic stellate cells (HSC) of rat liver: Involvement of HSC in recruitment of inflammatory cells during hepatic tissue repair.
Am. J. Pathol.
154
,
153
-167.

Kondo, T., and Kahn, C.R. (

2004
) Altered insulin signaling in retinal tissue in diabetic states.
J. Biol. Chem.
279
,
37997
-38006.

Kristensson, K., and Olsson, Y. (

1973
) Accumulation of protein tracers in pericytes of the central nervous system following systemic injection in immature mice.
Acta Neurol. Scand.
49
,
189
-194.

Lawson, N.D., Scheer, N., Pham, V.N., Kim, C.H., Chitnis, A.B., Campos-Ortega, J.A., and Weinstein, B.M. (

2001
) Notch signaling is required for arterial-venous differentiation during embryonic vascular development.
Development
128
,
3675
-3683.

Leveen, P., Pekny, M., Gebre-Medhin, S., Swolin, B., Larsson, E., and Betsholtz, C. (

1994
) Mice deficient for PDGF B show renal, cardiovascular, and hematological abnormalities.
Genes Dev.
8
,
1875
-1887.

Li, D.Y., Sorensen, L.K., Brooke, B.S., Urness, L.D., Davis, E.C., Taylor, D.G., Boak, B.B., and Wendel, D.P. (

1999
) Defective angiogenesis in mice lacking endoglin.
Science
284
,
1534
-1537.

Li, Z., Colucci-Guyon, E., Pincon-Raymond, M., Mericskay, M., Pournin, S., Paulin, D., and Babinet, C. (

1996
) Cardiovascular lesions and skeletal myopathy in mice lacking desmin.
Dev. Biol.
175
,
362
-366.

Lindahl, P., Johansson, B.R., Leveen, P., and Betsholtz, C. (

1997
) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice.
Science
277
,
242
-245.

Lindahl, P., Hellstrom, M., Kalen, M., and Betsholtz, C. (

1998
) Endothelial perivascular cell signaling in vascular development: Lessons from knockout mice.
Curr. Opin. Lipidol.
9
,
407
-411.

Lindblom, P., Gerhardt, H., Liebner, S., Abramsson, A., Enge, M., Hellstrom, M., Backstrom, G., Fredriksson, S., Landegren, U., Nystrom, H.C., Bergstrom, G., Dejana, E., Ostman, A., Lindahl, P., and Betsholtz, C. (

2003
) Endothelial PDGF-B retention is required for proper investment of pericytes in the microvessel wall.
Genes Dev.
17
,
1835
-1840.

Maisonpierre, P.C., Suri, C., Jones, P.F., Bartunkova, S., Wiegand, S.J., Radziejewski, C., Compton, D., McClain, J., Aldrich, T.H., Papadopou los, N., Daly, T.J., Davis, S., Sato, T.N., and Yancopoulos, G.D. (

1997
) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis.
Science
277
,
55
-60.

Majno, G., Palade, G.E., and Schoefl, G.I. (

1961
) Studies on inflammation: II. The site of action of histamine and serotonin along the vascular tree: A topographic study.
J. Cell Biol.
11
,
607
-626.

Mandarino, L.J., Sundarraj, N., Finlayson, J., and Hassell, H.R. (

1993
) Regulation of fibronectin and laminin synthesis by retinal capillary endo thelial cells and pericytes in vitro.
Exp. Eye Res.
57
,
609
-621.

Mandriota, S.J., Menoud, P.A., and Pepper, M.S. (

1996
) Transforming growth factor beta 1 down-regulates vascular endothelial growth factor receptor 2/fl k-1 expression in vascular endothelial cells.
J. Biol. Chem.
271
,
11500
-11505.

McLeod, D.S., Taomoto, M., Cao, J., Zhu, Z., Witte, L., and Lutty, G.A. (

2002
) Localization of VEGF receptor-2 (KDR/Flk-1) and effects of blocking it in oxygen-induced retinopathy.
Invest Ophthalmol. Vis. Sci.
43
,
474
-482.

Miller, J.W., Adamis, A.P., and Aiello, L.P. (

1997
) Vascular endothelial growth factor in ocular neovascularization and proliferative diabetic retinopathy.
Diabetes Metab. Rev.
13
,
37
-50.

Milner, D.J., Weitzer, G., Tran, D., Bradley, A., and Capetanaki, Y. (

1996
) Disruption of muscle architecture and myocardial degeneration in mice lacking desmin.
J. Cell Biol.
134
,
1255
-1270.

Morikawa, S., Baluk, P., Kaidoh, T., Haskell, A., Jain, R.K., and McDonald, D.M. (

2002
) Abnormalities in pericytes on blood vessels and endothe lial sprouts in tumors.
Am. J. Pathol.
160
,
985
-1000.

Nakajima, Y., Mironov, V., Yamagishi, T., Nakamura, H., and Markwald, R.R. (

1997
) Expression of smooth muscle alpha-actin in mesenchymal cells during formation of avian endocardial cushion tissue: A role for transforming growth factor beta3.
Dev. Dyn.
209
,
296
-309.

Orlidge, A., and D'Amore, P.A. (

1987
) Inhibition of capillary endothelial cell growth by pericytes and smooth muscle cells.
J. Cell Biol.
105
,
1455
-1462.

Ozerdem, U., Grako, K.A., Dahlin-Huppe, K., Monosov, E., and Stallcup, W.B. (

2001
) NG2 proteoglycan is expressed exclusively by mural cells during vascular morphogenesis.
Dev. Dyn.
222
,
218
-227.

Ozerdem, U., and Stallcup, W.B. (

2003
) Early contribution of pericytes to angiogenic sprouting and tube formation.
Angiogenesis
6
,
241
-249.

Ozerdem, U., and Stallcup, W.B. (

2004
) Pathological angiogenesis is reduced by targeting pericytes via the NG2 proteoglycan.
Angiogenesis
7
,
269
-276.

Pietras, K., and 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
,
939
-952.

Rajantie, I., Ilmonen, M., Alminaite, A., Ozerdem, U., Alitalo, K., and Sal ven, P. (

2004
) Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells.
Blood
104
,
2084
-2086.

Ramsauer, M., and D'Amore, P.A. (

2002
) Getting Tie(2)d up in angiogen esis.
J. Clin. Invest.
110
,
1615
-1617.

Reinmuth, N., Liu, W., Jung, Y.D., Ahmad, S.A., Shaheen, R.M., Fan, F., Bucana, C.D., McMahon, G., Gallick, G.E., and Ellis, L.M. (

2001
) Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival.
FASEB J.
15
,
1239
-1241.

Reynolds, L.P., Grazul-Bilska, A.T., and Redmer, D.A. (

2000
) Angiogenesis in the corpus luteum.
Endocrine
12
,
1
-9.

Ribatti, D., Vacca, A., Nico, B., Ria, R., and Dammacco, F. (

2002
) Cross-talk between hematopoiesis and angiogenesis signaling pathways.
Curr. Mol. Med.
2
,
537
-543.

Robbins, S.G., Rajaratnam, V.S., and Penn, J.S. (

1998
) Evidence for upregu lation and redistribution of vascular endothelial growth factor (VEGF) receptors fl t-1 and fl k-1 in the oxygen-injured rat retina.
Growth Factors
16
,
1
-9.

Ronnov-Jessen, L., and Petersen, O.W. (

1996
) A function for filamentous alpha-smooth muscle actin: Retardation of motility in fibroblasts.
J. Cell Biol.
134
,
67
-80.

Rucker, H.K., Wynder, H.J., and Thomas, W.E. (

2000
) Cellular mechanisms of CNS pericytes.
Brain Res. Bull.
51
,
363
-369.

Sato, M., Suzuki, S., and Senoo, H. (

2003
) Hepatic stellate cells: Unique characteristics in cell biology and phenotype.
Cell Struct. Funct.
28
,
105
-112.

Sato, Y., and Rifkin, D.B. (

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
,
309
-315.

Shaheen, R.M., Tseng, W.W., Davis, D.W., Liu, W., Reinmuth, N., Vellagas, R., Wieczorek, A.A., Ogura, Y., McConkey, D.J., Drazan, K.E., Bucana, C.D., McMahon, G., and Ellis, L.M. (

2001
) Tyrosine kinase inhibition of multiple angiogenic growth factor receptors improves survival in mice bearing colon cancer liver metastases by inhibition of endothelial cell survival mechanisms.
Cancer Res.
61
,
1464
-1468.

Sims, D.E. (

2000
) Diversity within pericytes.
Clin. Exp. Pharmacol. Physiol.
27
,
842
-846.

Smith, L.E., Wesolowski, E., McLellan, A., Kostyk, S.K., D'Amato, R., Sul livan, R., and D'Amore, P.A. (

1994
) Oxygen-induced retinopathy in the mouse.
Invest. Ophthalmol. Vis. Sci.
35
,
101
-111.

Song, S., Ewald, A.J., Stallcup, W., Werb, Z., and Bergers, G. (

2005
) PDGFRβ+ perivascular progenitor cells in tumours regulate pericyte diffentiation and survival.
Nat. Cell Biol.
[published online August 21], in press.

Soriano, P. (

1994
) Abnormal kidney development and hematological disor ders in PDGF beta-receptor mutant mice.
Genes Dev.
8
,
1888
-1896.

Stallcup, W.B. (

2002
) The NG2 proteoglycan: Past insights and future pros pects.
J. Neurocytol.
31
,
423
-435.

Suematsu, M., and Aiso, S. (

2001
) Professor Toshio Ito: A clairvoyant in pericyte biology.
Keio J. Med.
50
,
66
-71.

Sundberg, C., Kowanetz, M., Brown, L.F., Detmar, M., and Dvorak, H.F. (

2002
) Stable expression of angiopoietin-1 and other markers by cul tured pericytes: Phenotypic similarities to a subpopulation of cells in maturing vessels during later stages of angiogenesis in vivo.
Lab. Invest.
82
,
387
-401.

Suri, C., Jones, P.F., Patan, S., Bartunkova, S., Maisonpierre, P.C., Davis, S., Sato, T.N., and Yancopoulos, G.D. (

1996
) Requisite role of angio poietin-1, a ligand for the TIE2 receptor, during embryonic angiogen esis.
Cell
87
,
1171
-1180.

Thomas, W.E. (

1999
) Brain macrophages: On the role of pericytes and perivascular cells.
Brain Res. Brain Res. Rev.
31
,
42
-57.

Tilton, R.G., Kilo, C., and Williamson, J.R. (

1979
) Pericyte-endothelial relationships in cardiac and skeletal muscle capillaries.
Microvasc. Res.
18
,
325
-335.

Uemura, A., Ogawa, M., Hirashima, M., Fujiwara, T., Koyama, S., Takagi, H., Honda, Y., Wiegand, S.J., Yancopoulos, G.D., and Nishikawa, S. (

2002
) Recombinant angiopoietin-1 restores higher-order architecture of growing blood vessels in mice in the absence of mural cells.
J. Clin. Invest.
110
,
1619
-1628.

Verbeek, M.M., de Waal, R.M., Schipper, J.J., and Van Nostrand, W.E. (

1997
) Rapid degeneration of cultured human brain pericytes by amy loid beta protein.
J. Neurochem.
68
,
1135
-1141.

Vikkula, M., Boon, L.M., Carraway, K.L., 3rd, Calvert, J.T., Diamonti, A.J., Goumnerov, B., Pasyk, K.A., Marchuk, D.A., Warman, M.L., Cantley, L.C., Mulliken, J.B., and Olsen, B.R. (

1996
) Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2.
Cell
87
,
1181
-1190.

Wilkinson-Berka, J.L., Babic, S., De Gooyer, T., Stitt, A.W., Jaworski, K., Ong, L.G., Kelly, D.J., and Gilbert, R.E. (

2004
) Inhibition of platelet-derived growth factor promotes pericyte loss and angiogenesis in ische mic retinopathy.
Am. J. Pathol
164
,
1263
-1273.

Yamashita, J., Itoh, H., Hirashima, M., Ogawa, M., Nishikawa, S., Yurugi, T., Naito, M., Nakao, K., and Nishikawa, S. (

2000
) Flk1-positive cells derived from embryonic stem cells serve as vascular progenitors.
Nature
408
,
92
-96.

Zhong, T.P., Rosenberg, M., Mohideen, M.A., Weinstein, B., and Fishman, M.C. (

2000
) gridlock, an HLH gene required for assembly of the aorta in zebrafish.
Science
287
,
1820
-1824.

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Symposium on Angiogenesis, Part 2
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