... in development

During evolution, organisms have become capable of performing more and more complex tasks. To achieve this goal, they developed highly specialized tissues: a branched vascular system to ensure that all tissues receive adequate blood supply, and a structured nervous system in which nerves branch to transmit electrical signals to peripheral organs.

Recent evidence indicates that the development of both the nervous and vascular systems is controlled by a series of common developmental cues and mechanisms, more so than originally anticipated. Indeed, vessels and nerves use similar signals and principles to grow, differentiate, and navigate toward their final targets. Both systems also share several molecular pathways and cross-talk to each other, highlighting an important link between vascular biology and neuroscience. This neurovascular link is not only critical for development, but, when deregulated, contributes to the pathogenesis of medically relevant diseases. Studying the molecular nature of this link thus promises to accelerate the discovery of new pathogenetic insights and therapeutic strategies for the treatment of both vascular and neurological diseases.

Over the last years, the VRC has invested substantial efforts to elucidate this neurovascular link in health and disease. We study the development of both systems by using several vertebrate and invertebrate animal models, and have developed in vivo and ex vivo gene-manipulation techniques to study the consequences of gain- and loss-of-function approaches. Ongoing genetic studies focus on unraveling the role of VEGF as a guidance signal for granule cell neurons in the cerebellum, and how VEGF is required for the correct wiring of the cerebellar and other CNS circuits during development.

Additional projects involve the use of transgenic gain- and loss-of-function studies in fruitflies (D. melanogaster) to study the role of VEGF in neuronal survival, axon branching and synapse plasticity. An advantage of using the fruitfly model is that, apart from the powerful genetics this model offers, this small animal model does not contain a developed vasculature, thus allowing one to study the neuronal activity of VEGF in the absence of its vascular effects.

... in disease

Using advanced mouse genetics, we recently documented that the prototypic angiogenic factor VEGF is important for survival of adult motoneurons. Indeed, mice expressing low levels of VEGF suffer paralyzing motoneurodegeneration, resembling amytrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease. Additional human as well as mouse genetic studies confirmed the role of VEGF in motoneuron degeneration. We further showed that intramuscular VEGF viral gene transfer and intracerebroventricular (ICV) VEGF protein delivery prolonged the survival of rodent models of ALS by preserving their lower motoneurons. Clinical trials testing the therapeutic potential of ICV delivery of VEGF in individuals with ALS will be initiated in 2008.

We will now further investigate the mechanisms whereby VEGF promotes survival of adult motoneurons, i.e. via effects on blood vessels (perfusion, structure, angiogenesis) or on neurons (direct neuroprotective effects, or indirectly through effects on glia, etc), using conditional gene inactivation approaches. The VRC will also study the effect and therapeutic potential of other VEGF family members, using similar genetic and gene / protein transfer techniques. Translational studies investigating whether these findings in the mouse are also relevant for ALS patients are underway.

We will also investigate whether VEGF has a similar neuroprotective role in other neurodegenerative disorders, such as Parkinson’s Disease, Alzheimer’s Disease and multiple sclerosis. These investigations will be complemented with studies of other critical neuronal survival factors such as the inhibitor of apoptosis protein (IAP) survivin – a downstream effector of VEGF – in neural development and neurovascular disease using novel combinatorial approaches. The possible role and therapeutic potential of other angiogenic factors in neurodegeneration are also being evaluated.

Peter Carmeliet