Cellular and molecular mechanism of vascular malformations

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Vascular malformations are alterations in blood vessel morphology and function. They can affect all blood vessel types and range in severity from being asymptomatic to life-threatening. In this application I plan to study Cerebral Cavernous Malformations (CCMs) a disease in which capillary-venous malformations form within the central nervous system. CCM lesions can measure several centimeter in size and affected blood vessels are prone to leak. While CCM is a rare disease, it is devastating for affected individuals that 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. My host laboratory has recently shown that the small GTPase CDC42 plays a key role in the pathophysiology of CCM and has developed a CDC42 based animal model to study this disease. Preliminary results suggest the novel concept that endothelial cell migration defects initiate the formation of malformations. Whereas other processes subsequently contribute to lesion expansion and growth. With the experiments outlined in this application I aim to specifically investigate if cell migration defects also contribute to lesion formation in other CCM mouse models and to characterize the cellular and molecular mechanisms that underlay the subsequent lesion expansion. Using single-cell RNA sequencing experiments I will map the transcriptional changes in Cdc42 depleted endothelial cells with the aim to identify potential therapeutic targets as well as useful biomarkers that can help to diagnose the initial steps of lesion formation. I will also study the morphogenetic events and dynamics of lesion formation using intravital imaging. The proposed studies are likely to significantly increase our knowledge about the cellular and molecular mechanisms by which CCM- vascular malformations arise. The gained knowledge, in turn, will be instrumental in designing pharmacological treatment strategies for CCMs.