Article
Deficiency of Yes – associated protein 1 (YAP) expression in brain arteriovenous malformations – impact on the angioarchitecture and therapy
Mangelnde Yes – associated protein 1 (YAP) Expression in cerebralen arteriovenösen Malformationen: Einfluss auf die Angioarchitektur und Therapie
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Authors
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Mohammad Ali Karimpour
- Universitätsklinikum Magdeburg, Klinik für Neurochirurgie, Magdeburg, Deutschland
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Belal Neyazi
- Universitätsklinikum Magdeburg, Klinik für Neurochirurgie, Magdeburg, Deutschland
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Klaus-Peter Stein
- Universitätsklinikum Magdeburg, Klinik für Neurochirurgie, Magdeburg, Deutschland
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Karl Hartmann
- Universitätsklinikum Magdeburg, Klinik für Neurochirurgie, Magdeburg, Deutschland
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Christian Mawrin
- Universitätsklinikum Magdeburg, Institut für Neuropathologie, Magdeburg, Deutschland
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Claudia A. Dumitru
- Universitätsklinikum Magdeburg, Klinik für Neurochirurgie, Magdeburg, Deutschland
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I. Erol Sandalcioglu
- Universitätsklinikum Magdeburg, Klinik für Neurochirurgie, Magdeburg, Deutschland
| Published: | May 25, 2022 |
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Outline
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Objective: Brain arteriovenous malformations (bAVM) are rare vascular lesions and as such a recurring cause of intracerebral hemorrhage in young patients. The underlying cellular and molecular mechanisms associated with the pathogenesis of bAVM are still unknown. Yap acts not only as a mechanotransducer, as its role in developmental angiogenesis is critical. Targeted loss of YAP at early postnatal days showed less vascular density with tortuous and enlarged capillaries and numerous microaneurysm formations at the vascular branching region in the brains of mice. The phenotype in these mice resembles the phenotype of human bAVM. The role of YAP in the pathophysiology of bAVM is currently unknown. In our study, we assessed the expression of YAP in bAVM vessels compared to control vessels as well as its expression in relation to different clinical parameters.
Methods: The protein expression of YAP, Connective tissue growth factor (CTGF), Cysteine-rich angiogenic inducer 61 (CYR61), Hypoxia-inducible Factor - 1α (HIF-1α) and Fibroblast Growth Factor Receptor 1 (FGFR1) expression was analysed by immunohistochemistry on 130 paraffin-embedded AVM sections. Healthy cerebral vessels of 17 specimens were used as control group.
Results: The levels of YAP (p = < 0.001) and its downstream targets CTGF (p = < 0.001) and CYR61 (p = < 0.001) were significantly higher in the control vessels than in vessels of bAVM. In bAVM patients treated with embolization prior to surgery (n = 20), the expression levels of YAP (p = 0.05), CTGF (p = < 0.001) and CYR61 (p = < 0.001) were significantly higher than in patients who did not undergo previous endovascular treatment (n = 110). Additionally, we analyzed the expression of HIF-1α and FGFR1 as possible upstream factors inducing YAP in embolized bAVM. Both HIF-1α (p = < 0.001) and FGFR1 (p = 0,024) were significantly upregulated in embolized bAVM specimens.
Conclusion: This study reports for the first time the expression of YAP, CTGF and CYR61 in bAVM and suggests a potential role in bAVM pathophysiology. Decreased activation of YAP during developmental angiogenesis due to upstream factors may lead to the pathogenesis of bAVM. Additionally, our findings suggest that incomplete embolization induce the expression of these pro-angiogenic factors. Further studies have to evaluate the effects of these changes in the microenvironment of bAVM.
