MPDZ promotes DLL4-induced Notch signaling during angiogenesis.

Blood vessels transport oxygen and nutrients to all our organs and also remove waste products. New blood vessels form – in a process called angiogenesis – when a tissue is not receiving enough oxygen. This happens during normal development and wound healing, but also during tumor growth. Cells at the tip of a branching blood vessel sense when a tissue lacks oxygen and use proteins on their cell surfaces to help new vessels to grow. During this process, the tip cells of an existing vessel relay the signal from the tissue to other cells ‘behind’ them, in the so-called stalk of the vessel. It is known that tip- and stalk cells communicate by using specific proteins at their interfaces. The tip cells activate proteins called Notch ligands, such as DLL4, while stalk cells express the Notch receptor. During a process called Notch signaling, the ligands bind to the receptor, which becomes active and helps to control angiogenesis. It also hinders excessive vessel branching and so prevents the blood vessels from becoming leaky and inefficient. However, it was not known exactly how Notch ligands interact with their receptors on neighboring cells, and Notch signaling is regulated. Here, Tetzlaff et al. sought to answer these questions by using blood vessel cells from the human umbilical cord grown in the laboratory and blood vessel cells in mice. The results showed that the proteins DLL1 and DLL4 interacted with a protein called MPDZ. This interaction stabilized the DLL proteins at the cell membrane, which increased the Notch-signaling activity. When Tetzlaff et al. experimentally reduced the amount of MPDZ in the laboratory-grown cells, the Notch signaling decreased. Furthermore, the cells with less MPDZ formed more branching structures. And when MPDZ was genetically removed in mice, the embryos had more branched blood vessels in their developing brains. Lastly, when mice without MPDZ were transplanted with tumor cells, the tumors contained more, but leakier, blood vessels and were not supplied with enough oxygen. This suggests that MPDZ is an important factor that helps to regulate angiogenesis by enhancing Notch signaling between tip and branch cells in a new blood vessel. The increased activity of the Notch limits new blood vessels from branching too much. A better understanding of how blood vessels form or become leaky may help to find ways to prevent tumors from growing.