Figure 4.
Figure 4. ADAMTS13 regulates neovascularization and vascular permeability through the Ang-2/Gal-3–mediated VEGFR-2 phosphorylation. (A) Quantitative PCR was used in freshly isolated brain microvessels to evaluate the expression of molecules potentially important for vascular integrity in WT and Adamts13−/− mice 10 days after stroke. CTGF, connective tissue growth factor; IGFBP7, insulin-like growth factor binding protein-7; IL-8, interleukin-8; osteo, osteoprotegerin. Values are mean ± SD. Unpaired, 2-tailed Student t test. n = 3 per group, *P < .05. (B) Quantitative PCR was used in freshly isolated brain microvessels to evaluate the expression of Ang-2 and Gal-3 in WT and Vwf−/− mice 10 days after stroke. Values are mean ± SD. Unpaired 2-tailed Student t test. n = 3 per group, *P < .05. (C-F) Quantification of percent area occupied by vascular structures, perfused capillary length, PDGFR-β+ pericyte coverage, and the PS product of FITC-dextran in Adamts13−/− mice treated with control (Ad-Con) or Ang-2 adenoviruses (Ad-Ang-2), and Ad-Ang-2 in combination with dimethyl sulfoxide (DMSO) or the VEGFR-2 antagonist Su1498. Values are mean ± SD. One-way ANOVA followed by Bonferroni multiple comparison test. n = 6 per group, *P < .05. (G-J) Quantification of percent area occupied by vascular structures, perfused capillary length, PDGFR-β+ pericyte coverage, and the PS product of FITC-dextran in Adamts13−/− mice treated with saline or rGal-3, rGal-3 in combination with DMSO or the VEGFR-2 antagonist Su1498. Values are mean ± SD. One-way ANOVA followed by Bonferroni multiple comparison test. n = 6 per group, *P < .05. (K) (Left) Immunoblots of VEGFR-2 and phosphorylated VEGFR-2 in brain microvessels of WT mice, Adamts13−/− mice, Adamts13−/− mice treated with Ad-Con or Ad-Ang-2, Adamts13−/− mice treated with saline or rGal-3, Vwf−/− mice, and WT mice treated with vehicle or rADAMTS13. (Right) Quantitative determination of phosphorylated VEGFR-2 in brain microvessels for each group. Values are mean ± SD. n = 5 per group. *P < .05, One-way ANOVA followed by Bonferroni multiple comparison test. #P < .05, Unpaired, 2-tailed Student t test. (L) ADAMTS13 regulates angiogenesis and vascular remodeling by targeting VWF. ADMATS13 deficiency results in enhanced plasma UL-VWF and suppressed Ang-2/Gal-3–pVEGFR-2 signaling and as a consequence impaired vascular remodeling and functional recovery.

ADAMTS13 regulates neovascularization and vascular permeability through the Ang-2/Gal-3–mediated VEGFR-2 phosphorylation. (A) Quantitative PCR was used in freshly isolated brain microvessels to evaluate the expression of molecules potentially important for vascular integrity in WT and Adamts13−/− mice 10 days after stroke. CTGF, connective tissue growth factor; IGFBP7, insulin-like growth factor binding protein-7; IL-8, interleukin-8; osteo, osteoprotegerin. Values are mean ± SD. Unpaired, 2-tailed Student t test. n = 3 per group, *P < .05. (B) Quantitative PCR was used in freshly isolated brain microvessels to evaluate the expression of Ang-2 and Gal-3 in WT and Vwf−/− mice 10 days after stroke. Values are mean ± SD. Unpaired 2-tailed Student t test. n = 3 per group, *P < .05. (C-F) Quantification of percent area occupied by vascular structures, perfused capillary length, PDGFR-β+ pericyte coverage, and the PS product of FITC-dextran in Adamts13−/− mice treated with control (Ad-Con) or Ang-2 adenoviruses (Ad-Ang-2), and Ad-Ang-2 in combination with dimethyl sulfoxide (DMSO) or the VEGFR-2 antagonist Su1498. Values are mean ± SD. One-way ANOVA followed by Bonferroni multiple comparison test. n = 6 per group, *P < .05. (G-J) Quantification of percent area occupied by vascular structures, perfused capillary length, PDGFR-β+ pericyte coverage, and the PS product of FITC-dextran in Adamts13−/− mice treated with saline or rGal-3, rGal-3 in combination with DMSO or the VEGFR-2 antagonist Su1498. Values are mean ± SD. One-way ANOVA followed by Bonferroni multiple comparison test. n = 6 per group, *P < .05. (K) (Left) Immunoblots of VEGFR-2 and phosphorylated VEGFR-2 in brain microvessels of WT mice, Adamts13−/− mice, Adamts13−/− mice treated with Ad-Con or Ad-Ang-2, Adamts13−/− mice treated with saline or rGal-3, Vwf−/− mice, and WT mice treated with vehicle or rADAMTS13. (Right) Quantitative determination of phosphorylated VEGFR-2 in brain microvessels for each group. Values are mean ± SD. n = 5 per group. *P < .05, One-way ANOVA followed by Bonferroni multiple comparison test. #P < .05, Unpaired, 2-tailed Student t test. (L) ADAMTS13 regulates angiogenesis and vascular remodeling by targeting VWF. ADMATS13 deficiency results in enhanced plasma UL-VWF and suppressed Ang-2/Gal-3–pVEGFR-2 signaling and as a consequence impaired vascular remodeling and functional recovery.

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