Soluble endoglin modulates aberrant cerebral vascular remodeling

Yongmei Chen, Qi Hao, Helen Kim, Hua Su, Michelle Letarte, S. Ananth Karumanchi, Michael T. Lawton, Nicholas M. Barbaro, Guo Yuan Yang, William L. Young

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Objective: Brain arteriovenous malformations (AVMs) are an important cause of neurological morbidity in young adults. The pathophysiology of these lesions is poorly understood. A soluble form of endoglin (sEng) has been shown to cause endothelial dysfunction and induce preeclampsia. We tested if sEng would be elevated in brain AVM tissues relative to epilepsy brain tissues, and also investigated whether sEng overexpression via gene transfer in the mouse brain would induce vascular dysplasia and associated changes in downstream signaling pathways. Methods: Expression levels of sEng in surgical specimens were determined by Western blot assay and enzyme-linked immunosorbent assay. Vascular dysplasia, levels of matrix metalloproteinase (MMP), and oxidative stress were determined by immunohistochemistry and gelatin zymography. Results: Brain AVMs (n = 33) had higher mean sEng levels (245 ± 175 vs 100 ± 60, % of control, p = 0.04) compared with controls (n = 8), as determined by Western blot. In contrast, membrane-bound Eng was not significantly different (108 ± 79 vs 100 ± 63, % of control, p = 0.95). sEng gene transduction in the mouse brain induced abnormal vascular structures. It also increased MMP activity by 490 ± 30% (MMP-9) and 220 ± 30% (MMP-2), and oxidants by 260 ± 20% (4-hydroxy-2-nonenal) at 2 weeks after injection, suggesting that MMPs and oxidative radicals may mediate sEng-induced pathological vascular remodeling. Interpretation: The results suggest that elevated sEng may play a role in the generation of sporadic brain AVMs. Our findings may provide new targets for therapeutic intervention for patients with brain AVMs.

Original languageEnglish (US)
Pages (from-to)19-27
Number of pages9
JournalAnnals of neurology
Volume66
Issue number1
DOIs
StatePublished - Jul 1 2009

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Fingerprint Dive into the research topics of 'Soluble endoglin modulates aberrant cerebral vascular remodeling'. Together they form a unique fingerprint.

  • Cite this

    Chen, Y., Hao, Q., Kim, H., Su, H., Letarte, M., Karumanchi, S. A., Lawton, M. T., Barbaro, N. M., Yang, G. Y., & Young, W. L. (2009). Soluble endoglin modulates aberrant cerebral vascular remodeling. Annals of neurology, 66(1), 19-27. https://doi.org/10.1002/ana.21710