Endothelial heparan sulfate in angiogenesis.
Heparan sulfate (HS) is a linear polysaccharide composed of 50-200 glucosamine and uronic acid (glucuronic acid or iduronic acid) disaccharide repeats with epimerization and various sulfation modifications. HS is covalently attached to core proteins to form HS-proteoglycans. Most of the functions of HS-proteoglycans are mediated by their HS moieties. The biosynthesis of HS is initiated by chain polymerization and is followed by stepwise modification reactions, including sulfation and epimerization. These modifications generate ligand-binding sites that modulate cell functions and activities of proteinases and/or proteinase inhibitors. HS is abundantly expressed in developing and mature vasculature, and understanding its roles in vascular biology and related human diseases is an area of intense investigation. In this chapter, we summarize the significant recent advances in our understanding of the roles of HS in developmental and pathological angiogenesis with a major focus on studies using transgenic as well as gene knockout/knockdown models in mice and zebrafish. These studies have revealed that HS critically regulates angiogenesis by playing a proangiogenic role, and this regulatory function critically depends on HS fine structure. The latter is responsible for facilitating cell-surface binding of various proangiogenic growth factors that in turn mediate endothelial growth signaling. In cancer, mouse studies have revealed important roles for endothelial cell-surface HS as well as matrix-associated HS, wherein signaling by multiple growth factors as well as matrix storage of growth factors may be regulated by HS. We also discuss important mediators that may fine-tune such regulation, such as heparanase and sulfatases; and models wherein targeting HS (or core protein) biosynthesis may affect tumor growth and vascularization. Finally, the importance of targeting HS in other human diseases wherein angiogenesis may play pathophysiologic (or even therapeutic) roles is considered.
Fuster
Mark M
MM
Department of Medicine, Division of Pulmonary and Critical Care, University of California San Diego, La Jolla, California, USA.
Wang
Lianchun
L
D000818:Animals; D004730:Endothelium, Vascular / Q000378:metabolism*; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic
D006497:Heparan Sulfate
J Biol Chem. 2009 Aug 7;284(32):21505-14
19520866
Growth Factors. 2009 Feb;27(1):22-31
19107652
Am J Pathol. 2004 Jul;165(1):35-52
15215160
Biochem Biophys Res Commun. 2005 Aug 5;333(3):976-83
15985216
J Biol Chem. 2001 May 18;276(20):17014-21
11278892
Genes Dev. 2003 Aug 1;17(15):1835-40
12897053
FASEB J. 1999 Jan;13(1):9-22
9872925
J Biol Chem. 2002 Sep 6;277(36):32970-7
12087088
N Engl J Med. 2000 Mar 2;342(9):626-33
10699162
J Cell Biol. 2003 Jun 23;161(6):1163-77
12810700
Nat Immunol. 2005 Sep;6(9):902-10
16056228
Biochim Biophys Acta. 2002 Dec 19;1573(3):209-15
12417402
Annu Rev Biochem. 1999;68:729-77
10872465
Methods Cell Biol. 2002;69:83-109
12071011
J Clin Invest. 2001 Jul;108(2):175-80
11457868
Curr Pharm Des. 2009;15(25):2946-57
19754371
N Engl J Med. 2006 Dec 14;355(24):2542-50
17167137
Dev Biol. 2000 Aug 15;224(2):299-311
10926768
N Engl J Med. 2004 Jun 3;350(23):2335-42
15175435
Blood. 2010 Mar 25;115(12):2449-57
20097882
Curr Opin Hematol. 2003 Mar;10(2):131-5
12579039
EMBO J. 1998 Jun 1;17(11):3005-15
9606183
Birth Defects Res C Embryo Today. 2003 Feb;69(1):73-82
12768659
Cell. 1996 Dec 27;87(7):1171-80
8980224
Cancer Res. 2004 Jul 15;64(14):4699-702
15256433
Dev Biol. 2005 Aug 15;284(2):364-76
16009360
JACC Cardiovasc Imaging. 2009 Jul;2(7):869-79
19608138
Gastroenterology. 2004 Jan;126(1):231-48
14699503
J Cell Biol. 2001 Nov 26;155(5):845-58
11724824
Mol Cell Biol. 2000 Oct;20(19):7282-91
10982845
Circ Res. 2003 Sep 5;93(5):429-37
12919949
Genes Dev. 2002 Oct 15;16(20):2684-98
12381667
Dev Dyn. 2007 Feb;236(2):556-63
17183530
FASEB J. 2005 Feb;19(2):211-21
15677344
J Biol Chem. 1996 Mar 29;271(13):7788-95
8631822
Nature. 2008 Dec 11;456(7223):809-13
18997771
Cell Mol Life Sci. 2004 Sep;61(17):2224-43
15338053
Prog Retin Eye Res. 2009 Mar;28(2):117-44
19114125
Vasc Endovascular Surg. 2005 Jul-Aug;39(4):293-306
16079938
Cell Regul. 1991 Jul;2(7):503-12
1782212
J Cell Sci. 2001 Mar;114(Pt 5):853-65
11181169
J Med Chem. 2010 Feb 25;53(4):1686-99
20128596
Science. 2003 Nov 7;302(5647):1044-6
14605369
Neoplasia. 2005 Nov;7(11):1001-10
16331886
J Cell Biol. 2001 Apr 30;153(3):543-53
11331305
Hum Pathol. 1998 Sep;29(9):910-4
9744306
Nature. 2005 Dec 15;438(7070):937-45
16355211
J Biol Chem. 2000 Feb 25;275(8):5249-52
10681494
Glycobiology. 2005 Oct;15(10):982-93
15944372
FEBS J. 2008 Aug;275(16):4074-87
18631173
Proc Natl Acad Sci U S A. 2002 Nov 26;99(24):15451-5
12432102
Nature. 1999 Aug 19;400(6746):773-6
10466727
Cytokine Growth Factor Rev. 2005 Apr;16(2):159-78
15863032
J Biol Chem. 1997 Jul 18;272(29):18000-6
9218427
Biochem Soc Trans. 2006 Jun;34(Pt 3):458-60
16709187
J Biol Chem. 2007 May 25;282(21):15578-88
17405882
Circulation. 2007 Oct 23;116(17):1896-906
17923576
Cancer Res. 2001 Aug 15;61(16):6050-4
11507052
Swiss Med Wkly. 2006 Sep 16;136(37-38):583-90
17043951
Mol Cancer Res. 2008 Jan;6(1):1-9
18234958
Cell Mol Life Sci. 2006 Nov;63(21):2435-45
16952056
Glycobiology. 2002 Nov;12(11):721-7
12460940
Science. 1997 Jul 11;277(5323):242-5
9211853
Curr Pharm Des. 2007;13(20):2057-73
17627539
Graefes Arch Clin Exp Ophthalmol. 2009 Jun;247(6):767-73
19247683
Curr Opin Hematol. 2004 Jul;11(4):278-83
15314528
Ophthalmic Res. 2007;39(3):139-42
17505145
Int J Biochem Cell Biol. 2006;38(12):2018-39
16901744
Nat Med. 1995 Jan;1(1):27-31
7584949
Cancer Microenviron. 2008 Dec;1(1):131-9
19308691
J Biol Chem. 2008 Jan 25;283(4):2335-43
18024432
Nature. 2005 Dec 15;438(7070):932-6
16355210
J Exp Med. 2009 Mar 16;206(3):691-705
19255147
Cell Tissue Res. 2009 Jan;335(1):261-9
18766380
Nat Med. 1996 May;2(5):534-9
8616711
J Clin Invest. 2001 Aug;108(3):349-55
11489925
Nature. 2007 Apr 26;446(7139):1030-7
17460664
Nature. 2000 Sep 14;407(6801):242-8
11001067
Annu Rev Biochem. 2002;71:435-71
12045103
Development. 2005 Aug;132(16):3777-86
16020517
Pharmacol Rev. 2000 Jun;52(2):237-68
10835101
Biochem Soc Trans. 2003 Apr;31(2):340-2
12653633
J Clin Invest. 2003 Oct;112(8):1142-51
14561699
J Cell Biol. 2007 May 7;177(3):539-49
17470635
Cancer Res. 2006 Jun 15;66(12):6025-32
16778174
Matrix Biol. 2005 Jan;23(8):557-61
15694132
Nature. 1996 Apr 4;380(6573):435-9
8602241
Blood. 2009 Jul 23;114(4):915-24
19398718
Genes Dev. 1991 Jul;5(7):1191-9
2065974
J Clin Invest. 2004 Mar;113(6):885-94
15067321
Circ Res. 2005 Sep 16;97(6):512-23
16166562
J Biol Chem. 2006 May 26;281(21):14813-22
16481316
PLoS Med. 2008 Jan 29;5(1):e19
18232728
EMBO J. 2008 Apr 9;27(7):993-1004
18337748
Cancer Res. 2009 Aug 1;69(15):6057-64
19584297
Nature. 1995 Jul 6;376(6535):62-6
7596435
J Invest Dermatol. 1996 Nov;107(5):676-83
8875948
J Clin Invest. 2001 Aug;108(3):341-7
11489924
Nat Rev Cancer. 2006 Aug;6(8):626-35
16837971
J Clin Invest. 2006 Oct;116(10):2610-21
17016557
FASEB J. 2005 May;19(7):716-28
15857886
J Cell Biol. 1998 May 4;141(3):805-14
9566978
J Clin Invest. 2001 Jan;107(2):R9-R14
11160142
Nat Med. 1999 May;5(5):495-502
10229225
Nature. 1997 Apr 17;386(6626):671-4
9109485
J Biol Chem. 2000 Aug 25;275(34):25926-30
10852901
Curr Diabetes Rev. 2006 Feb;2(1):71-98
18220619
J Biol Chem. 2007 May 4;282(18):13326-33
17347152
J Biol Chem. 2007 Sep 7;282(36):26418-30
17580303
J Immunol. 2003 Feb 15;170(4):2147-52
12574387
Biochem Soc Trans. 2006 Jun;34(Pt 3):451-3
16709184
J Clin Invest. 2001 Jul;108(2):169-73
11457867
Microsc Res Tech. 2003 Jan 1;60(1):107-14
12500267
EXS. 2005;(94):163-80
15617478
Nature. 1992 Oct 29;359(6398):843-5
1279431
J Cell Sci. 2002 May 1;115(Pt 9):1951-9
11956326
Dev Cell. 2006 May;10(5):625-34
16678777
Curr Opin Lipidol. 2008 Jun;19(3):307-13
18460924
J Biol Chem. 2000 Aug 11;275(32):24653-60
10816596
N Engl J Med. 2004 Dec 30;351(27):2805-16
15625332
J Biol Chem. 2003 Aug 1;278(31):28363-6
12788935
J Clin Invest. 2003 Apr;111(7):989-99
12671048
Genesis. 2008 Jan;46(1):8-18
18196599
Biochim Biophys Acta. 2002 Dec 19;1573(3):312-8
12417413
N Engl J Med. 1994 Dec 1;331(22):1480-7
7526212
Nat Chem Biol. 2007 Dec;3(12):773-8
17952066
Mol Cell. 2004 Mar 12;13(5):649-63
15023336
Genes Dev. 2007 Feb 1;21(3):316-31
17289920
Cancer Cell. 2004 Nov;6(5):485-95
15542432
Retina. 2006 Oct;26(8):859-70
17031284
Nat Med. 2003 Jun;9(6):685-93
12778167
J Biol Chem. 2004 Oct 8;279(41):42732-41
15292174
Ann Rheum Dis. 2008 May;67(5):592-601
17545191
FEBS Lett. 2000 Feb 4;467(1):7-11
10664446
Int J Dev Biol. 2000 Apr;44(3):253-65
10853822
Nature. 1995 Jul 6;376(6535):66-70
7596436
Cell. 1998 Mar 20;92(6):735-45
9529250
J Biol Chem. 2010 Feb 19;285(8):5907-16
20022960