Endothelial Cell Cytoprotection
Histological and immunohistochemical analysis of Matrigel implants
Professor Justin Mason, Principal Investigator
As a consequence of its anatomic location at the blood/tissue interface, the vascular endothelium is continuously exposed to potentially harmful factors such as endotoxin, cytokines, complement components, activated leukocytes and oxidatively modified low-density lipoproteins. These factors may contribute to chronic endothelial dysfunction and premature atherosclerosis. Professor Mason leads a basic science research group investigating molecular mechanisms involved in the regulation of vascular endothelial cytoprotection. A more detailed understanding of these mechanisms will facilitate the rational design of novel therapies by which the endothelium can be conditioned in order to minimise vascular injury, endothelial dysfunction and subsequent atherogenesis in patients with systemic inflammatory disease. In addition, he is actively involved in clinical research, which aims to optimise assessment and treatment of the large vessel vasculitides and understand the relationship between chronic endothelial dysfunction and accelerated atherosclerosis.
Summary of laboratory research
The principal aim of Professor Mason’s scientific research is to extend understanding of the molecular mechanisms involved in vascular endothelial cytoprotection and the maintenance of vascular integrity. A second aspect is to explore the overlap between mechanisms regulating cytoprotection and those involved in reparative angiogenesis. To this end, vascular endothelial growth factor has been an important area of recent study in light of its cytoprotective and pro-angiogenic actions.
In recent years Professor Mason’s group has delineated signalling pathways regulating the expression of decay-accelerating factor and CD59 and has identified them as inducible regulators of complement activation on the endothelial cell surface, which enhance cytoprotection against complement-mediated injury. This led to work identifying VEGF-R2, PKCα, PKCε and p38 MAPK as key components of the VEGF-induced signalling pathway for DAF regulation, and the demonstration that the immunosuppressive drugs cyclosporin A and rapamycin have differential effects on this pathway. Subsequent studies have demonstrated that PKCε acts downstream of PI-3K and forms a signalling complex with Akt, acting co-dependently to protect primary human vascular EC against apoptosis, through induction of the anti-apoptotic protein Bcl-2 and inhibition of caspase-3 cleavage.
The development of a model in the laboratory through which endothelial cells can be exposed to prolonged laminar or oscillatory shear stress has allowed a more physiologically relevant in vitro model to be developed and led to the demonstration that CD59 expression is differentially regulated by laminar and oscillatory flow both in vitro and in vivo. This approach will be further developed in future projects.
Using in vitro and in vivo models of angiogenesis in collaboration with Professor B Bussolati (University of Turin), Professor Mason has demonstrated that during chronic inflammation the cytoprotective gene heme oxygenase-1 has two roles; (i) first an anti-inflammatory action inhibiting leukocyte infiltration and (ii) promotion of VEGF-driven non-inflammatory angiogenesis which facilitates tissue repair. The actions of HO-1 in vascular endothelium and its potential as a therapeutic target form an important component of future work for the group.
Summary of clinical research
Professor Mason is also actively involved in clinical research, in collaboration with colleagues at Hammersmith Hospital (Dr A Al-Nahhas), Northwick Park Hospital (Dr J Andrews), The Royal Brompton (Professor D Pennell and Dr R Mohiaddin) and in the Division of Clinical Sciences (Professor P Camici and Dr O Rimoldi), which aims to optimise clinical assessment and management of large vessel vasculitis and to understand the relationship between chronic endothelial dysfunction and accelerated atherosclerosis. The combined aim of the research effort is to establish a more detailed understanding of the mechanisms regulating vascular cytoprotection, in order to facilitate the rational design of novel therapies by which vascular endothelium can be conditioned to minimise vascular injury, EC dysfunction and subsequent atherogenesis in patients with systemic inflammatory disease.
Current projects
The group is currently funded by the British Heart Foundation, the Arthritis Research Campaign and the Hammersmith Hospital Trustees:
ADDITIONAL COLLABORATORS:Dr B Bussolati (University of Turin, Italy)Dr M Ohba (Showa University, Japan) Dr A Samarel (Loyola University, USA) Dr M Soares (Gulbenkian Institute, Portugal) Dr J Gavrilovic (University of East Anglia, UK) Dr C Wheeler-Jones (Royal Veterinary College, UK) Professor A Ahmed (University of Birmingham, UK) Professor P Bacon (University of Birmingham, UK) Dr P Jat (University College London, UK) Professor C Rajkumar (Brighton and Sussex Medical School, UK) |
