Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

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  • Bin Xu
    From the Departments of Anesthesia and Perioperative Care, Duke University Medical Center, Durham, North Carolina, U.S.A.
  • Yong Qin Wu
    From the Departments of Anesthesia and Perioperative Care, Duke University Medical Center, Durham, North Carolina, U.S.A.
  • Madeleine Huey
    From the Departments of Anesthesia and Perioperative Care, Duke University Medical Center, Durham, North Carolina, U.S.A.
  • Helen M. Arthur
    Institute of Human Genetics, University of Newcastle, United Kingdom
  • Douglas A. Marchuk
    Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, North Carolina, U.S.A.
  • Tomoki Hashimoto
    From the Departments of Anesthesia and Perioperative Care, Duke University Medical Center, Durham, North Carolina, U.S.A.
  • William L. Young
    From the Departments of Anesthesia and Perioperative Care, Duke University Medical Center, Durham, North Carolina, U.S.A.
  • Guo-Yuan Yang
    From the Departments of Anesthesia and Perioperative Care, Duke University Medical Center, Durham, North Carolina, U.S.A.

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<jats:p> Hereditary hemorrhagic telangiectasia (HHT), associated with brain arteriovenous malformations, is caused by a loss of function mutation in either the endoglin (HHT1) or activin receptor-like kinase 1 gene (ALK-1, HHT2). Endoglin heterozygous ( Eng<jats:sup>+/−</jats:sup>)mice have been proposed as a disease model. To better understand the role of endoglin in vascular malformation development, we examined the effect of vascular endothelial growth factor (VEGF) hyperstimulation on microvessels in adult endoglin heterozygous ( Eng<jats:sup>+/−</jats:sup>) mice using an adenoviral vector to deliver recombinant human VEGF<jats:sub>165</jats:sub> cDNA (Ad hVEGF) into basal ganglia. VEGF expression was increased in Ad hVEGF mice compared with the Ad lacZ and saline group ( P < 0.05) and localized to multiple cell types (neurons, astrocytes, endothelial cells, and smooth muscle cells) by double-labeled immunostaining. VEGF overexpression increased microvessel count for up to 4 weeks in both the Eng<jats:sup>+/+</jats:sup> and Eng<jats:sup>+/+</jats:sup> groups ( Eng<jats:sup>+/+</jats:sup> 185 ± 14 vs. Eng<jats:sup>+/−</jats:sup> 201 ± 10 microvessels/mm<jats:sup>2</jats:sup>). Confocal microscopic examination revealed grossly abnormal microvessels in eight of nine Eng<jats:sup>+/−</jats:sup> mouse brains compared with zero of nine in Eng<jats:sup>+/+</jats:sup> mice ( P < 0.05). Abnormal microvessels featured enlargement, clustering, twist, or spirals. VEGF receptor Flk-1 and TGF-β receptor 1 (TβR1) expression were reduced in the Eng<jats:sup>+/−</jats:sup> mouse brain compared with control. </jats:p><jats:p> Excessive VEGF stimulation may play a pivotal role in the initiation and development of brain vessel malformations in states of relative endoglin insufficiency in adulthood. These observations are relevant to our general understanding of the maintenance of vascular integrity. </jats:p>

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