1. Analysis of In Situ and Ex Vivo Vascular Endothelial Growth Factor Receptor Expression During Experimental Aortic Aneurysm Progression
- Author
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Maureen M. Tedesco, Francis G. Blankenberg, Ronald L. Dalman, Joseph M. Backer, Marina V. Backer, Joshua M. Spin, Mien Sho, Eiketsu Sho, Michael V. McConnell, Masahiro Terashima, and Zoia Levashova
- Subjects
Pathology ,medicine.medical_specialty ,Angiogenesis ,medicine.medical_treatment ,Angiogenesis Inhibitors ,Article ,Fluorescence ,Mice ,chemistry.chemical_compound ,Aortic aneurysm ,Apolipoproteins E ,Growth factor receptor ,medicine ,Animals ,Vascular Endothelial Growth Factor Receptor-1 ,Neovascularization, Pathologic ,business.industry ,Growth factor ,Kinase insert domain receptor ,Anatomy ,medicine.disease ,Vascular Endothelial Growth Factor Receptor-2 ,Angiotensin II ,Mice, Inbred C57BL ,Vascular endothelial growth factor ,Disease Models, Animal ,chemistry ,Doxycycline ,cardiovascular system ,Cardiology and Cardiovascular Medicine ,business ,Ex vivo ,Aortic Aneurysm, Abdominal - Abstract
Objective— Mural inflammation and neovascularization are characteristic pathological features of abdominal aortic aneurysm (AAA) disease. Vascular endothelial growth factor receptor (VEGFR) expression may also mediate AAA growth and rupture. We examined VEGFR expression as a function of AAA disease progression in the Apolipoprotein E–deficient (Apo E −/− ) murine AAA model. Methods and Results— Apo E −/− mice maintained on a high-fat diet underwent continuous infusion with angiotensin II at 1000 ng/kg/min (Ang II) or vehicle (Control) via subcutaneous osmotic pump. Serial transabdominal ultrasound measurements of abdominal aortic diameter were recorded (n=16 mice, 3 to 4 time points per mouse) for up to 28 days. Near-infrared receptor fluorescent (NIRF) imaging was performed on Ang II mice (n=9) and Controls (n=5) with scVEGF/Cy, a single-chain VEGF homo-dimer labeled with Cy5.5 fluorescent tracer (7 to 18 μg/mouse IV). NIRF with inactivated single chain VEGF/Cy tracer (scVEGF/In, 18 μg/mouse IV) was performed on 2 additional Ang II mice to control for nonreceptor-mediated tracer binding and uptake. After image acquisition and sacrifice, aortae were harvested for analysis. An additional AAA mouse cohort received either an oral angiogenesis inhibitor or suitable negative or positive controls to clarify the significance of angiogenesis in experimental aneurysm progression. Aneurysms developed in the suprarenal aortic segment of all Ang II mice. Significantly greater fluorescent signal was obtained from aneurysmal aorta as compared to remote, uninvolved aortic segments in Ang II scVEGF/Cy mice or AAA in scVEGF/In mice or suprarenal aortic segments in Control mice. Signal intensity increased in a diameter-dependent fashion in aneurysmal segments. Immunostaining confirmed mural VEGFR-2 expression in medial smooth muscle cells. Treatment with an angiogenesis inhibitor attenuated AAA formation while decreasing mural macrophage infiltration and CD-31 + cell density. Conclusion— Mural VEGFR expression, as determined by scVEGF/Cy fluorescent imaging and VEGFR-2 immunostaining, increases in experimental AAAs in a diameter-dependent fashion. Angiogenesis inhibition limits AAA progression. Clinical VEGFR expression imaging strategies, if feasible, may improve real-time monitoring of AAA disease progression and response to suppressive strategies.
- Published
- 2009
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