The research, by Paolo Madeddu, Professor of Experimental Cardiovascular Medicine and his team in the Bristol Heart Institute (BHI) at the University of Bristol, was funded by the British Heart Foundation and is published in the leading journal Circulation Research.
Ischaemia occurs when the blood supply to a tissue is impaired as a result of hardening of the arteries in the heart, known as atherosclerosis. It can also occur in poorly managed diabetes, causing ischaemia in other areas of the body, such as the legs. If the tissue is to recover, the blood supply needs to be restored, and angiogenesis is a critical part of this process.
“Notch” is a protein-receptor found on cell membranes that is important in regulating communication between neighbouring cells “cell-cell crosstalk”. Notch is particularly important in regulating normal vascular development, being part of the genetic program that ensures arteries and veins develop correctly. Although it is known that the Notch receptor regulates blood vessel formation during development, little is known about whether it is important in regulating blood vessel formation following ischaemia (reparative angiogenesis).
Like all receptors, Notch requires binding of another molecule (ligand) to become active; these ligands are found on neighbouring cells. In this study the team found that one of these ligands, a protein known as “Dll4”, was present in only small quantities in normal blood vessels. But, following induction of heart or back leg ischaemia in mice, Dll4 was found to be present at remarkably high amounts in blood vessels following ischaemia, particularly at the front of the new endothelial cells that would form mature blood vessels.
Inhibiting Dll4, so that the Notch receptor was no longer activated, caused the formation of a disorganised, low-perfused blood vessel network in the ischaemia heart and muscle, and eventually muscle degeneration. Another problem that occurred after inhibiting Dll4 was that there was an enhanced inflammatory response to ischaemia – the muscles became infiltrated with leukocytes (a type of white blood cell) because of the activation of a specific cytokine mechanism.
Professor Paolo Madeddu said: “Our findings reveal a novel mechanism that co-ordinates new blood vessels and inflammation in ischemia to ensure proper healing. But future studies are needed to verify whether dysregulation of this mechanism contributes to inefficient angiogenesis and prolongation of inflammation in ischemic disease.”
These results demonstrate that the Dll4-Notch interaction is fundamental for the formation of a functional vascular network in ischaemic tissues. Moreover, Dll4/Notch signalling plays an important role in coordinating inflammation and angiogenesis to the aim of ensuring proper tissue healing.
Paper: Inhibition of Delta-Like-4–Mediated Signaling Impairs Reparative Angiogenesis After Ischemia, Ayman Al Haj Zen, Atsuhiko Oikawa, Miriam Bazan-Peregrino, Marco Meloni, Costanza Emanueli, Paolo Madeddu, Circulation Research, published online May 27, 2010.