Cellular and molecular mechanism of vascular malformations
Cardiology, Angiology
Pathology
Final Report Abstract
Cerebral Cavernous Malformations (CCMs) is a disease in which capillary-venous malformations form within the central nervous system (CNS). Affected individuals experience severe symptoms including headaches, vision and hearing loss, seizures and paralysis. At present, there is no pharmacological treatment available and the mechanisms that lead to lesion formation remain, in many aspects, poorly understood. CCMs can arise sporadically but also have a genetic component. Three genes have been linked to the familiar variants of the disease CCM1 (KRIT1), CCM2 and CCM3 (PDCD10). It is currently assumed that the disease is caused by the loss of heterozygosity through a second hit somatic mutation that results in a loss of both alleles of either CCM1, CCM2 or CCM3. In addition, recent studies also indicate that gain of functions PI3K mutations are required to fuel the aggressive growth of CCMs. The fact that CCMs remain restricted to capillary-venous regions of the vasculature and mainly occur in the CNS is remarkable. However, in about 9% of patients, CCMs are also observed in the skin. Skin lesions are seldom described in the literature and poorly understood and have, thus far, not been described in animal models of CCM. Here we report, that endothelial cellspecific postnatal deletion of Ccm3 (CCM3iECKO) triggers the development of vascular malformations in the ear skin of mice. These skin malformations recapitulate the characteristic features of CNS lesions and also remain restricted to capillaries and veins. Intravital imaging of CCM skin lesions confirms that those are slow-flow malformations showing a reduced perfusion. A limitation of conventional CCM models, in which CCM gene deletion is induced at early postnatal stages, is that most of them are lethal within 3 weeks and that malformations mainly occur in the cerebellum. This makes live imaging of malformations very difficult. In contrast, the ear skin suits itself ideally for intravital imaging as it easy accessible and flat. Importantly it can be used for longitudinal studies. Taken together, the Ccm3iECKO ear skin model recapitulates major hallmarks of CNS lesions and is therefore a valuable tool to study CCM development and most likely efficiencies of pharmacological treatments.
Publications
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Mural Cell SRF Controls Pericyte Migration, Vessel Patterning and Blood Flow. Circulation Research, 131(4), 308-327.
Orlich, Michael M.; Diéguez-Hurtado, Rodrigo; Muehlfriedel, Regine; Sothilingam, Vithiyanjali; Wolburg, Hartwig; Oender, Cansu Ebru; Woelffing, Pascal; Betsholtz, Christer; Gaengel, Konstantin; Seeliger, Mathias; Adams, Ralf H. & Nordheim, Alfred
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Age‐Associated Changes in Endothelial Transcriptome and Epigenetic Landscapes Correlate With Elevated Risk of Cerebral Microbleeds. Journal of the American Heart Association, 12(17).
Mohan, Kshitij; Gasparoni, Gilles; Salhab, Abdulrahman; Orlich, Michael M.; Geffers, Robert; Hoffmann, Steve; Adams, Ralf H.; Walter, Jörn & Nordheim, Alfred
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Incongruence between transcriptional and vascular pathophysiological cell states. Nature Cardiovascular Research, 2(6), 530-549.
Fernández-Chacón, Macarena; Mühleder, Severin; Regano, Alvaro; Garcia-Ortega, Lourdes; Rocha, Susana F.; Torroja, Carlos; Sanchez-Muñoz, Maria S.; Lytvyn, Mariya; Casquero-Garcia, Verónica; De Andrés-Laguillo, Macarena; Muhl, Lars; Orlich, Michael M.; Gaengel, Konstantin; Camafeita, Emilio; Vázquez, Jesús; Benguría, Alberto; Iruela-Arispe, M. Luisa; Dopazo, Ana; Sánchez-Cabo, Fátima ... & Benedito, Rui
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Mural Serum Response Factor (SRF) Deficiency Provides Insights into Retinal Vascular Functionality and Development. International Journal of Molecular Sciences, 24(16), 12597.
Günter, Alexander; Sothilingam, Vithiyanjali; Orlich, Michael M.; Nordheim, Alfred; Seeliger, Mathias W. & Mühlfriedel, Regine
