Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina.
Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein-coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of S1P 2 receptor (S1P2R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P2R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2-/- mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2-/- mouse retina. S1P2R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P2R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P2R may be a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization.
Skoura
Athanasia
A
Center for Vascular Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.
Sanchez
Teresa
T
Claffey
Kevin
K
Mandala
Suzanne M
SM
Proia
Richard L
RL
Hla
Timothy
T
D000818:Animals; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012164:Retinal Diseases / Q000378:metabolism* / Q000473:pathology*
D049349:Receptors, Lysosphingolipid; D052250:Nitric Oxide Synthase Type III; D051546:Cyclooxygenase 2
J Exp Med. 2001 Mar 5;193(5):607-20
11238591
Science. 1998 Mar 6;279(5356):1552-5
9488656
Circ Res. 2001 Sep 28;89(7):583-90
11577023
Cancer Res. 2002 Feb 1;62(3):625-31
11830509
Anal Biochem. 2002 Apr 15;303(2):167-75
11950216
Circulation. 2002 Jul 2;106(1):57-62
12093770
J Cell Physiol. 2002 Aug;192(2):182-7
12115724
Nat Med. 2002 Sep;8(9):1004-10
12145646
J Clin Invest. 2002 Dec;110(11):1729-38
12464678
J Biol Chem. 2002 Dec 20;277(51):50081-6
12401798
Invest Ophthalmol Vis Sci. 2003 Mar;44(3):974-9
12601017
Science. 2003 Mar 14;299(5613):1740-3
12637747
Nat Rev Mol Cell Biol. 2003 May;4(5):397-407
12728273
J Cell Biol. 2003 Jun 23;161(6):1163-77
12810700
J Clin Invest. 2003 Jul;112(1):50-7
12840058
Circulation. 2003 Jul 15;108(2):198-204
12821538
J Exp Med. 2003 Aug 4;198(3):483-9
12900522
J Biol Chem. 2003 Nov 21;278(47):47281-90
12954648
Nat Chem Biol. 2006 Aug;2(8):434-41
16829954
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14537-41
16983080
Nat Med. 1999 Dec;5(12):1418-23
10581086
Nature. 2000 Jul 13;406(6792):192-5
10910360
J Cell Physiol. 2000 Sep;184(3):275-84
10911358
J Clin Invest. 2000 Oct;106(8):951-61
11032855
Invest Ophthalmol Vis Sci. 2001 Jan;42(1):222-8
11133872
Cell. 1998 May 29;93(5):705-16
9630216
J Clin Invest. 1998 Jun 15;101(12):2711-9
9637705
Biochem Biophys Res Commun. 1999 Jan 19;254(2):292-8
9918831
J Biol Chem. 1999 Sep 24;274(39):27351-8
10488065
Int J Dev Biol. 2004;48(8-9):1045-58
15558494
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4312-7
15764699
Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10999-1004
16043715
J Immunol. 2005 Dec 1;175(11):7151-61
16301618
Nature. 2005 Dec 15;438(7070):960-6
16355161
Cancer Res. 2006 Jan 1;66(1):221-31
16397235
Annu Rev Pharmacol Toxicol. 2006;46:235-76
16402905
J Clin Invest. 2006 Feb;116(2):369-77
16424942
Invest Ophthalmol Vis Sci. 2006 Mar;47(3):1126-41
16505051
Biochem J. 2006 Aug 1;397(3):461-71
16623665
Proc Natl Acad Sci U S A. 2004 Jan 13;101(2):591-6
14688410
Circ Res. 2004 Apr 2;94(6):724-34
15059942
J Pharmacol Exp Ther. 2004 May;309(2):758-68
14747617
J Biol Chem. 2004 Jul 9;279(28):29367-73
15138255
J Cell Biochem. 2004 Aug 1;92(5):913-22
15258915
Semin Cell Dev Biol. 2004 Oct;15(5):513-20
15271296
Am J Pathol. 2004 Oct;165(4):1301-13
15466395
Invest Ophthalmol Vis Sci. 2006 Nov;47(11):5022-31
17065523
Diabetes. 2006 Dec;55(12):3573-80
17130506
J Clin Invest. 2006 Dec;116(12):3266-76
17111048
Gene Expr Patterns. 2007 Feb;7(4):461-70
17161657
J Neurosci. 2007 Feb 7;27(6):1474-8
17287522
Nature. 2007 Feb 15;445(7129):776-80
17259973
J Biol Chem. 2007 Apr 6;282(14):10690-6
17284444
J Clin Invest. 2004 Oct;114(8):1082-9
15489955
Genes Dev. 2004 Oct 1;18(19):2392-403
15371328
Arterioscler Thromb Vasc Biol. 2007 Jun;27(6):1312-8
17431187
Microvasc Res. 1988 Nov;36(3):275-90
2466191
Invest Ophthalmol Vis Sci. 1994 Jan;35(1):101-11
7507904
Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):905-9
7846076
Proc Natl Acad Sci U S A. 1995 Nov 7;92(23):10457-61
7479819
J Clin Invest. 1995 Dec;96(6):2661-6
8675632
Am J Physiol. 1996 Dec;271(6 Pt 2):H2547-62
8997316
J Clin Invest. 2001 Mar;107(6):717-25
11254671