Elisabetta Dejana's research projects on vascular biology and angiogenesis
The role of adhesion proteins at cell to cell junctions in angiogenesis and vascular stabilization
Endothelial cells form monolayers linked one to another by adhesive molecules present at cell-to-cell junctions. During our research, we have identified two novel proteins expressed in endothelial cells that are responsible for cell-to-cell adhesion. They are called vascular endothelial cadherin (VE-cadherin) and junctional adhesion molecule (JAM).
Inactivation of the gene encoding VE-cadherin, or inhibition of its adhesive properties by specific antibodies, inhibits new vessel formation and tumor progression in experimental systems. We have observed that VE-cadherin, besides its adhesive properties, acts upon the regulation of cell growth and death and influences the ability of cells to form tubular structures. We have also identified a series of trans-membrane and cytoplasmic partners that combine with VE-cadherin to transfer intracellular signals and affect the expression of many endothelial genes.
Several of the proteins encoded by these genes regulate endothelial cell growth and apoptosis and constitute potential targets for drug interventions geared towards the inhibition of angiogenesis. Our future project deals with the study of the mechanism of action of these proteins and their reciprocal relationship.
The role of Wnt signaling in vascular development
Early stages of vascular development include endothelial cell differentiation in a network of arteries, veins, and lymphatics. Subsequently, to respond to the specific needs of the organs, endothelial cells acquire specialized properties such as permeability control, expression of specific trans-cellular transport systems, membrane adhesive molecules, and others. Endothelial cell differentiation depends on communication between the surrounding tissues, which is mediated by growth and differentiation factors able to activate specific gene expression programs.
Recent reports underline the important role of the Wnt system in vascular morphogenesis in the embryo and in organ-specific endothelial differentiation. Wnt signaling regulates fundamental aspects of development, including cell fate specification, proliferation, and survival, and may use different receptors and signaling pathways.
In our work we study the role of both loss- and gain-of-function mutants of members of the so called canonic Wnt signaling pathway. We have found alterations of vascular development and endothelial cell specification. Wnt signaling in the endothelium may also contribute to pathological conditions such as retinopathies, stroke, and tumor vascularization. We are engaged in studies directed to the mechanism of action of this pathway and of the downstream transcription factors.
Cerebral Cavernous Malformations (CCM)
CCM is a genetic, familial or sporadic, disease characterized by vascular malformations concentrated in the central nervous system, typically formed by multiple lumens and prone to bleeding. This pathology may result in several neurological symptoms, including headaches, seizures, paralyses and hemorrhagic stroke. CCM is the most frequent cause of hemorrhagic stroke in infancy. To date the only therapy available is surgery (Figure 3). However, surgery is frequently hazardous depending on the location of the vascular malformation.
In humans, loss of function mutations in any one of three independent genes known as CCM1 (Krit 1), CCM2 (MGC4607) and CCM3 (PDCD10) have been linked to the development of CCM. The vascular phenotype is largely superimposable in patients missing any one of the three genes.
Similarly to patients, in murine models, the vascular phenotype can be reproduced by endothelium-specific loss-of-function mutations of any one of these three CCM genes suggesting that they act in concert. Although CCM genes are expressed in the endothelium of different types of vessels the vascular malformations are present predominantly, if not only, in the brain microcirculation.
In our research work we observed that the endothelial cells lining the vascular CCM malformations change their morphological and functional characteristics, acquiring mesenchymal markers and elongated morphology. We found that two major signaling pathways (Wnt and TGF beta) are responsible for these changes of endothelial cells. Inhibitors of these pathways were found to prevent the endothelial to mesenchymal switch and the development of the CCM malformations.
Studies are under way to identify available drugs able to inhibit the development of CCM malformations or to induce their regression.