Soluble endoglin modulates aberrant cerebral vascular remodeling

• Published in: Annals of neurology 2009-07, Vol.66 (1), p.19-27
• Main Authors: Chen, Yongmei, Hao, Qi, Kim, Helen, Su, Hua, Letarte, Michelle, Karumanchi, S. Ananth, Lawton, Michael T., Barbaro, Nicholas M., Yang, Guo-Yuan, Young, William L.
• Format: Article
• Language: English
• Subjects: Adult; Aldehydes - pharmacology; Animals; Antigens, CD - metabolism; Biological and medical sciences; Central Nervous System Vascular Malformations - metabolism; Central Nervous System Vascular Malformations - pathology; Cysteine Proteinase Inhibitors - pharmacology; Disease Progression; Endoglin; Endothelium, Vascular - metabolism; Endothelium, Vascular - physiopathology; Enzyme-Linked Immunosorbent Assay - methods; Female; Gene Expression Regulation, Enzymologic - drug effects; Gene Expression Regulation, Enzymologic - physiology; Humans; Male; Malformations of Cortical Development - chemically induced; Matrix Metalloproteinases - classification; Matrix Metalloproteinases - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Neurology; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Receptors, Cell Surface - metabolism; Statistics, Nonparametric; Superoxides - metabolism; Vascular diseases and vascular malformations of the nervous system; Vascular Endothelial Growth Factor A - genetics; Young Adult
• ISSN: 0364-5134; 1531-8249
• DOI: 10.1002/ana.21710

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