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Transcriptional regulation of endothelial blood brain barrier differentiation by Wnt signaling

Final Report Summary - WNT FOR BRAIN (Transcriptional regulation of endothelial blood brain barrier differentiation by Wnt signaling)

The brain vasculature has evolved to protect the central nervous system from the constantly changing milieu in the blood stream. Endothelial cells of brain capillaries form the so-called blood brain barrier (BBB), an active permeability barrier and transport system that allows a selective passage of nutrients from blood to the nervous tissue. This highly specialized vascular system, however, constitute a formidable fence to small molecular drugs, recombinant proteins and antibodies strongly limiting therapeutic interventions for pathologies of the nervous system, including Alzheimer, multiple sclerosis or brain tumors. Conversely, an altered blood brain barrier is the cause of edema or hemorrhages in different diseases such as ischemic or hemorrhagic stroke.
The continuous cross talk of endothelial cells, pericytes and nervous cells influences many vascular functions and determines and maintains the BBB characteristics after birth. Our limited knowledge of the nature of these signals prevents the development of tools to reversibly “open” or “close” the vascular barrier.
In the present project we approached this problem by studying the transcriptional signaling that direct BBB differentiation. Specifically, we took advantage from a previous work of our group showing that the Wnt/β-catenin signaling system is required for triggering brain vascularization and BBB differentiation. We also found that few members of the Wnt family are released by the nervous cells surrounding the endothelium that promote in this way BBB differentiation and stability. Within this project, we studied more deeply the mechanism of action of canonical Wnt signalling in inducing BBB properties. We identified other transcription factors induced by Wnt that mediate non only the induction but also the maintenance of BBB properties. In addition, from gene profile studies we defined a set of Wnt target proteins that collaborate non only in the maintenance of the BBB but, most importantly, in restoration of BBB properties in case of damage. From all the work performed and the information collected we were also able to set up a standardized system in vitro using immortalized endothelial cells from human and mouse brain microcirculation. This system is an invaluable tool to perform large screening of drugs or recombinant agents to select those able to cross the BBB or to change its permeability properties. Finally the acquired knowledge on the development of the BBB was applied to the understating of the signaling pathways implicated in a human pathology called Cerebral Cavernous Malformation. This pathology, which has a prevalence in the population of 0,2-0,5 %, is characterized by the formation of cavernomas in the brain microcirculation that tend to break and eventually cause hemorrhagic stroke even in infancy. These patients have the only option to undergo surgery to remove the vascular cavernomas, but surgery may be dangerous depending on the location of the malformations. Through our research we have been able to identify some of the key pathways implicated in the development of the cavernomas and to design pharmacological inhibitors able to counteract and reduce this phenomenon. These studies open the possibility of a pharmacological therapy for this so far incurable disease.