SB-267268, a nonpeptidic antagonist of alpha(v)beta3 and alpha(v)beta5 integrins, reduces angiogenesis and VEGF expression in a mouse model of retinopathy of prematurity.
OBJECTIVE
To determine whether SB-267268, a nonpeptidic antagonist of the alpha(v)beta3 and alpha(v)beta5 integrins, attenuates angiogenesis in a murine model of retinopathy of prematurity (ROP) and alters the expression of vascular endothelial growth factor (VEGF) and its second receptor (VEGF-R2).


METHODS
In receptor binding, SB-267268 exhibited nanomolar potency for human, monkey, and murine alpha(v)beta3 and alpha(v)beta5. SB-267268 inhibited the attachment of alpha(v)beta3-transfected HEK293 cells to microtiter plate wells precoated with RGD-containing matrix proteins, and vitronectin-mediated human and rat aortic smooth-muscle-cell migration. At postnatal day (P)12, C57BL/6 mice were exposed to 80% oxygen for 7 days followed by 7 days in room air (angiogenic period). Between P12 and P17, ROP mice were administered sterile saline (vehicle intraperitoneal [i.p.]) or SB-267268 (60 mg/kg bi-daily, i.p.). Shams were exposed to room air from P0 and administered either vehicle or SB-267268 during P12 to 17. In at least 3 randomly chosen paraffin sections from each eye, the number of blood vessel profiles in the inner retina were counted. In situ hybridization for VEGF and VEGFR-2 was performed on at least 8 randomly chosen paraffin sections from each eye.


RESULTS
SB-267268 reduced pathologic angiogenesis in ROP mice by approximately 50% and had no effect on developmental retinal angiogenesis in shams. Both VEGF and VEGFR-2 mRNA were upregulated in the inner retina of ROP mice and reduced with SB-267268.


CONCLUSIONS
Nonpeptidic inhibition of alpha(v)beta3 and alpha(v)beta5 integrins is effective in ROP and may be a suitable anti-angiogenic therapy for other ischemic retinal pathologies.
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.jlaberka@unimelb.edu.au
Jennifer L
JL
Wilkinson-Berka
Daria
D
Jones
George
G
Taylor
Kassie
K
Jaworski
Darren J
DJ
Kelly
Steve B
SB
Ludbrook
Robert N
RN
Willette
Sanjay
S
Kumar
Richard E
RE
Gilbert
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001552:Benzazepines / Q000627:therapeutic use*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007231:Infant, Newborn; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D016023:Integrins / Q000037:antagonists & inhibitors*; D008251:Macaca; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors*; D015861:Retinal Neovascularization / Q000188:drug therapy* / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000188:drug therapy* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D001552:Benzazepines; D039302:Integrin alphaVbeta3; D016023:Integrins; D012333:RNA, Messenger; D019030:Receptors, Vitronectin; C509729:SB-267268; D042461:Vascular Endothelial Growth Factor A; C064660:integrin alphaVbeta5; C467480:vascular endothelial growth factor A, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2