Soluble endoglin modulates aberrant cerebral vascular remodeling†
Yongmei Chen MD, PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Yongmei Chen and Qi Hao contributed equally to this article.
Search for more papers by this authorQi Hao PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Yongmei Chen and Qi Hao contributed equally to this article.
Search for more papers by this authorHelen Kim PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Search for more papers by this authorHua Su MD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Search for more papers by this authorMichelle Letarte PhD
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Search for more papers by this authorS. Ananth Karumanchi MD
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Search for more papers by this authorMichael T. Lawton MD
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Search for more papers by this authorNicholas M. Barbaro MD
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Search for more papers by this authorGuo-Yuan Yang MD, PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Search for more papers by this authorCorresponding Author
William L. Young MD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Department of Neurology, University of California San Francisco, San Francisco, CA
UCSF Dept of Anesthesia and Perioperative Care, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110Search for more papers by this authorYongmei Chen MD, PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Yongmei Chen and Qi Hao contributed equally to this article.
Search for more papers by this authorQi Hao PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Yongmei Chen and Qi Hao contributed equally to this article.
Search for more papers by this authorHelen Kim PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Search for more papers by this authorHua Su MD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Search for more papers by this authorMichelle Letarte PhD
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
Search for more papers by this authorS. Ananth Karumanchi MD
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
Search for more papers by this authorMichael T. Lawton MD
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Search for more papers by this authorNicholas M. Barbaro MD
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Search for more papers by this authorGuo-Yuan Yang MD, PhD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Search for more papers by this authorCorresponding Author
William L. Young MD
Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California San Francisco, San Francisco, CA
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA
Department of Neurology, University of California San Francisco, San Francisco, CA
UCSF Dept of Anesthesia and Perioperative Care, 1001 Potrero Avenue, Room 3C-38, San Francisco, CA 94110Search for more papers by this authorPotential conflict of interest: Nothing to report.
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. Ann Neurol 2009;66:19–27
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