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.

Abstract

PURPOSE:

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.

• Authors: Jennifer L Wilkinson-Berka, Daria Jones, George Taylor, Kassie Jaworski, Darren J Kelly, Steve B Ludbrook, Robert N Willette, Sanjay Kumar, Richard E Gilbert
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 47 Issue 4 Pg. 1600-5 (Apr 2006) ISSN: 0146-0404 [Print] United States
• PMID: 16565398 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Benzazepines
• Integrin alphaVbeta3
• Integrins
• RNA, Messenger
• Receptors, Vitronectin
• SB-267268
• Vascular Endothelial Growth Factor A
• integrin alphaVbeta5
• vascular endothelial growth factor A, mouse
• Vascular Endothelial Growth Factor Receptor-2

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Benzazepines (therapeutic use)
• Cell Adhesion (drug effects)
• Cell Movement (drug effects)
• Disease Models, Animal
• Enzyme-Linked Immunosorbent Assay
• Female
• Gene Expression Regulation
• Humans
• Infant, Newborn
• Integrin alphaVbeta3 (antagonists & inhibitors)
• Integrins (antagonists & inhibitors)
• Macaca
• Mice
• Mice, Inbred C57BL
• Pregnancy
• RNA, Messenger (metabolism)
• Rats
• Receptors, Vitronectin (antagonists & inhibitors)
• Retinal Neovascularization (drug therapy, metabolism)
• Retinopathy of Prematurity (drug therapy, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (genetics, metabolism)