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Phosphatase and tensin homolog in cerebral cavernous malformation: a potential role in pathological angiogenesis


Zhu, Y; Peters, C; Hallier-Neelsen, M; Miller, D; Pagenstecher, A; Bertalanffy, H; Sure, U (2009). Phosphatase and tensin homolog in cerebral cavernous malformation: a potential role in pathological angiogenesis. Journal of Neurosurgery, 40(3):820-826.

Abstract

Object Cerebral cavernous malformations (CCMs) are the most common vascular malformation of the central nervous system and involve dysregulated angiogenesis. However, the underlying mechanism of this disease is poorly understood. Phosphatase and tensin homolog (PTEN) plays a crucial role in regulating angiogenesis. The authors attempted to determine whether PTEN is involved in the pathological angiogenesis of CCM. Methods The authors used Western blot analysis and immunohistochemical methods to detect the expression of PTEN, PCNA, and P-Akt in the surgical specimens of CCMs and controls. The function of PTEN in cell proliferation was studied after PTEN silencing in endothelial cultures by using the short interfering RNA technique. Results Western blot analysis showed significant reduction of PTEN protein expression in CCMs compared with control brain tissue (p < 0.01). Immunohistochemical analysis confirmed PTEN insufficiency in 33% of vascular endothelia of CCMs, which was significantly higher than that of controls (2%, p < 0.01). Furthermore, PTEN insufficiency occurred more frequently in multiple CCMs (44%) and in small lesions (39%) than in single CCMs (28%, p < 0.05) and large lesions (30%, p < 0.05), respectively, suggesting a potential role of PTEN in the progression of the lesions. Of note, a negative correlation was observed between the expression of PTEN and PCNA in CCM endothelial cells. However, Akt was not constitutively activated in CCMs. Using cultured endothelial cells, the authors demonstrated that PTEN silencing by short interfering RNA increased Akt activation, PCNA expression, and cell proliferation (p < 0.001). Surprisingly, the PTEN silencing-mediated increase in endothelial proliferation was not reversed by the PI3K inhibitor wortmannin. Conclusions In this study, the authors report for the first time a significant PTEN insufficiency in CCM vessels associated with endothelial proliferation. The in vitro study provides direct evidence for a pivotal role of PTEN in regulating endothelial proliferation, most likely through a PI3K-independent pathway. The authors suggest that PTEN insufficiency is potentially involved in CCM by stimulating angiogenesis.

Abstract

Object Cerebral cavernous malformations (CCMs) are the most common vascular malformation of the central nervous system and involve dysregulated angiogenesis. However, the underlying mechanism of this disease is poorly understood. Phosphatase and tensin homolog (PTEN) plays a crucial role in regulating angiogenesis. The authors attempted to determine whether PTEN is involved in the pathological angiogenesis of CCM. Methods The authors used Western blot analysis and immunohistochemical methods to detect the expression of PTEN, PCNA, and P-Akt in the surgical specimens of CCMs and controls. The function of PTEN in cell proliferation was studied after PTEN silencing in endothelial cultures by using the short interfering RNA technique. Results Western blot analysis showed significant reduction of PTEN protein expression in CCMs compared with control brain tissue (p < 0.01). Immunohistochemical analysis confirmed PTEN insufficiency in 33% of vascular endothelia of CCMs, which was significantly higher than that of controls (2%, p < 0.01). Furthermore, PTEN insufficiency occurred more frequently in multiple CCMs (44%) and in small lesions (39%) than in single CCMs (28%, p < 0.05) and large lesions (30%, p < 0.05), respectively, suggesting a potential role of PTEN in the progression of the lesions. Of note, a negative correlation was observed between the expression of PTEN and PCNA in CCM endothelial cells. However, Akt was not constitutively activated in CCMs. Using cultured endothelial cells, the authors demonstrated that PTEN silencing by short interfering RNA increased Akt activation, PCNA expression, and cell proliferation (p < 0.001). Surprisingly, the PTEN silencing-mediated increase in endothelial proliferation was not reversed by the PI3K inhibitor wortmannin. Conclusions In this study, the authors report for the first time a significant PTEN insufficiency in CCM vessels associated with endothelial proliferation. The in vitro study provides direct evidence for a pivotal role of PTEN in regulating endothelial proliferation, most likely through a PI3K-independent pathway. The authors suggest that PTEN insufficiency is potentially involved in CCM by stimulating angiogenesis.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Neurosurgery
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:5 December 2009
Deposited On:16 Feb 2009 16:16
Last Modified:05 Apr 2016 13:01
Publisher:American Association of Neurological Surgeons
ISSN:0022-3085
Publisher DOI:https://doi.org/10.3171/2008.7.17626
PubMed ID:19061355

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