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Inhibition of VEGF (Vascular Endothelial Growth Factor)-A or its Receptor Activity Suppresses Experimental Aneurysm Progression in the Aortic Elastase Infusion Model.

  • Xu, Baohui1, 2
  • Iida, Yasunori1, 2
  • Glover, Keith J1, 2
  • Ge, Yingbin3
  • Wang, Yan4
  • Xuan, Haojun1, 2
  • Hu, Xiaolei1, 2
  • Tanaka, Hiroki1, 2
  • Wang, Wei1, 2
  • Fujimura, Naoki1, 2
  • Miyata, Masaaki5
  • Shoji, Takahiro1, 2
  • Guo, Jia1, 2
  • Zheng, Xiaoya1, 2
  • Gerritsen, Mary1, 2
  • Kuo, Calvin6, 2
  • Michie, Sara A7
  • Dalman, Ronald L1, 2
  • 1 From the Departments of Surgery (B.X., Y.I., K.J.G., H.X., X.H., H.T., W.W., N.F., T.S., J.G., X.Z., M.G., R.L.D.), Stanford University School of Medicine, Stanford, CA.
  • 2 the Cardiovascular Institute (B.X., Y.I., K.J.G., H.X., X.H., H.T., W.W., N.F., T.S., J.G., X.Z., M.G., C.K., R.L.D.), Stanford University School of Medicine, Stanford, CA.
  • 3 Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu, China (Y.G.). , (China)
  • 4 Neurosurgery (Y.W.), Stanford University School of Medicine, Stanford, CA.
  • 5 Department of Cardiology and Hypertension, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan (M.M.). , (Japan)
  • 6 Medicine (C.K.), Stanford University School of Medicine, Stanford, CA.
  • 7 Pathology (S.A.M.), Stanford University School of Medicine, Stanford, CA.
Published Article
Arteriosclerosis Thrombosis and Vascular Biology
Ovid Technologies Wolters Kluwer -American Heart Association
Publication Date
Aug 01, 2019
DOI: 10.1161/ATVBAHA.119.312497
PMID: 31294623


We examined the pathogenic significance of VEGF (vascular endothelial growth factor)-A in experimental abdominal aortic aneurysms (AAAs) and the translational value of pharmacological VEGF-A or its receptor inhibition in aneurysm suppression. Approaches and Results: AAAs were created in male C57BL/6J mice via intra-aortic elastase infusion. Soluble VEGFR (VEGF receptor)-2 extracellular ligand-binding domain (delivered in Ad [adenovirus]-VEGFR-2), anti-VEGF-A mAb (monoclonal antibody), and sunitinib were used to sequester VEGF-A, neutralize VEGF-A, and inhibit receptor tyrosine kinase activity, respectively. Influences on AAAs were assessed using ultrasonography and histopathology. In vitro transwell migration and quantitative reverse transcription polymerase chain reaction assays were used to assess myeloid cell chemotaxis and mRNA expression, respectively. Abundant VEGF-A mRNA and VEGF-A-positive cells were present in aneurysmal aortae. Sequestration of VEGF-A by Ad-VEGFR-2 prevented AAA formation, with attenuation of medial elastolysis and smooth muscle depletion, mural angiogenesis and monocyte/macrophage infiltration. Treatment with anti-VEGF-A mAb prevented AAA formation without affecting further progression of established AAAs. Sunitinib therapy substantially mitigated both AAA formation and further progression of established AAAs, attenuated aneurysmal aortic MMP2 (matrix metalloproteinase) and MMP9 protein expression, inhibited inflammatory monocyte and neutrophil chemotaxis to VEGF-A, and reduced MMP2, MMP9, and VEGF-A mRNA expression in macrophages and smooth muscle cells in vitro. Additionally, sunitinib treatment reduced circulating monocytes in aneurysmal mice. VEGF-A and its receptors contribute to experimental AAA formation by suppressing mural angiogenesis, MMP and VEGF-A production, myeloid cell chemotaxis, and circulating monocytes. Pharmacological inhibition of receptor tyrosine kinases by sunitinib or related compounds may provide novel opportunities for clinical aneurysm suppression.

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