Recalibrating Mechanotransduction in Vascular Malformations

European Coordinator:
  • Miikka VIKKULA, de Duve Institute (Belgium)
North American Coordinator:
  • Luisa IRUELA-ARISPE, Northwestern University Feinberg School of Medicine (USA)
  • Ondine CLEAVER, UT Southwestern Medical Center (USA)
  • Joseph PENNINGER, University of British Columbia (Canada)
  • Salim SEYFRIED, University of Potsdam (Germany)
  • Elisabeth TOURNIER-LASSERVE, Paris University – INSERM U1141 (France)

Vascular cells form a complex architecture of interconnected tubes optimized to support the body with oxygen and nutrients. Mechanical forces imposed by blood flow play a key role during development and maintenance of the vasculature. Scientists in this Leducq Transatlantic Network of Excellence (TNE) study pathologies in which vascular cells are unable to respond properly to flow forces. This is the case when mutations cause dysregulated RAS-MAPK and nitric oxide (NO) signaling within blood vessels, resulting in the development of vascular malformations / dysplasias. VMs lead to severe, life-long pain and other devastating effects, particularly after stroke or when located in inoperable regions of the brain. With the goal to advance therapeutics, we propose the novel idea to normalize vascular cell responses to blood flow by pharmacological modulation of RAS-MAPK and NO pathways, and their targets. Our international consortium brings together complementary expertise from groups in genetics, cell biology, biochemistry, molecular biology, and stem cell biology to explore the abnormal behavior of mutant vascular cells and devise strategies to correct them. Individually, each member of the team has been working either on the identification of relevant underlying mutations that impact vascular architecture, or the molecular characterization of VMs from the cellular to the organismal level. However, it is only together that they hold the ability to effectively tackle the problem and advance basic science discoveries into clinical applications. Another highly important focus of the consortium is to expose young to interdisciplinary strategies and skill sets necessary to solve complex questions related to these devastating diseases. The mission is not only to mentor young investigators within our teams but also to provide opportunities to external emerging scientists with interest in vascular biology and biomedicine.