International Network of Excellence on Brain Endothelium: A Nexus for Cerebral Small Vessel Disease

  • Martin DICHGANS, Klinikum der Universität München (Germany)
  • Frank FARACI, The University of Iowa (USA)
  • Christer BETSHOLTZ, Uppsala University (Sweden)
  • Elizabeth HILLMAN, Columbia University (USA)
  • Anne JOUTEL, INSERM Paris (France)
  • Mark NELSON, The University of Vermont State and Agricultural College (USA)
  • Dominik PAQUET, Hospital of the Ludwig Maximilian Universität München (Germany)

Small vessel disease (SVD) is a major cause of microinfarcts and microbleeds—types of stroke that often go undetected, but are major contributors to disability and dementia. Brain endothelial cells (BECs) integrate physiological signals, serving as focal points for normal brain function. Investigators of this network have identified genetic variants in humans that increase the risk for SVD and stroke, suggesting a major role for BECs in brain health. We have developed mice that express such variants in BECs and have shown that they exhibit SVD and brain injury that mimic those in humans. Hypertension is the leading risk factor for SVD. Our preliminary results suggest that, when combined with genetic variants in BECs, hypertension increases SVD and brain injury to a greater extent than either pathology alone. With these findings, models with clinically relevant phenotypes and unique technologies, we propose a Network of Excellence Program to define BEC-dependent mechanisms underlying SVD. We will (1) identify mechanisms linking risk genes for SVD and stroke to BEC dysfunction and brain injury; (2) test whether genetic predisposition synergizes with hypertension to augment BEC dysfunction and brain injury (“two-hit” model); and (3) determine whether BEC heterogeneity underlies differences in brain injury across regions. These novel questions are supported by state-of-the-art methods; unique models, including a human inducible pluripotent stem cell model of the neurovascular unit; and substantial preliminary data demonstrating feasibility. Multifaceted mentoring of early-career investigators will be implemented across the Network to train future leaders in these areas. Early independence will be further fostered by seed funds and exchange of Leducq fellows between labs. We are in a unique position to tackle these fundamental questions and significantly advance our understanding of BECs, their impact on brain health, and their potential as targets of novel therapies.