Mats Hellström's research projects on blood vessel formation

Characterization of novel regulators of blood vessel formation

Hiroshi Kaito, Anja Nitzsche, Chiara Testini

Although the importance of angiogenesis in pathological conditions is well established few blood vessel-specific drug targets have been identified and information is still limited about endothelial-specific molecular pathways. Hence, there is a great need to better characterize the process in order to provide new ideas for improved and novel therapies.

In the search for endothelial-specific regulators we have used several approaches, including expression profiling of mouse vasculature and other mouse tissues, zebrafish gene knock down, and screening of drug-like compounds in human cellular assays. This led to the identification of several new regulators of angiogenesis, including kiaa1274/x99384/Pald1 (or Paladin), a putative cytoplasmic phosphatase. Paladin is one of the first examples of a cytoplasmic, potential phosphatase with an endothelial-specific expression.

Analysing the function of Paladin in knock-out mice

We have generated a mouse knock-out for Paladin with a functional β-galactosidase reporter, verifying endothelial specificity in many mouse tissues. We have characterized the expression pattern of mouse and human Paladin during development and in cancer tissue. Paladin is preferentially expressed in the vasculature and shows a dynamic expression pattern changing from expression in capillaries and veins during development, to vascular smooth muscle cells in arteries in the adult organs.

The knock-out mice are viable and fertile. Our preliminary data show that Paladin knock-outs display increased vascular density in the postnatal retina. We plan to further study vascularization of normal tissues as well as tumours. We will also perform comprehensive biochemical and signal transduction analyses in vitro, including over-expression and siRNA knock down of Pald1.

Kinases belong to an important drug target class in oncology, which strongly suggests that our studies on Pald1 will contribute to the understanding of kinase/phosphatase signalling in general and angiogenesis/tumour angiogenesis in particular.

Photo: images of vasculature in the retina