A newly identified cellular and molecular mechanism can be exploited to induce productive and sustained angiogenesis in tissues that have become ischemic because of the reduction in blood supply, according to a team of scientists from the National Center for Cardiovascular Research (CNIC) led by Rui Benedito.
Till present, tissue regeneration treatments based on vascular growth factors have not succeeded in inducing sufficient angiogenesis, the process through which the body generates new blood vessels. The scientists published the result of their study in Nature Communications, and it suggests that it might be possible to manipulate the newly discovered mechanism to achieve optimal therapeutic angiogenesis.
The body's blood vessels are like roads and highways that connect cities and allow them to grow and operate. The blood vessel of the body is essential for the development and function of tissues. Inhibition of vessel growth is a fundamental therapeutic goal in cancer, whereas induction of angiogenesis has the potential of promoting the formation of new blood vessels and tissue regeneration in cardiovascular disease.
For the past two decades, scientists have demonstrated that proper growth of blood vessel in each tissue depends on a correct balance of several molecular proangiogenic and antiangiogenic mechanisms, ischemic or hypoxic tissues secrete endothelial growth factors (VEGF), which promote angiogenesis by inducing the proliferation and migration of vascular cells. A past study by Rui Benedito's team showed that blood vessel cells resist and oppose these external mitogenic cues through an intercellular ligand-receptor signaling mechanism called Notch.
The recently prevailing view is that increases in VEGF concentration or decreases in vascular Notch signaling stimulate both vascular cell proliferation and vessel growth. Therefore, strategies aimed at stimulating mitogenesis and angiogenesis to treat cardiovascular disease are based on drugs that promote VEGF-signaling or block natural angiogenesis inhibitors such as Notch.
The result of the study indicates that high mitogenic stimulation induced by VEGF (or Notch inhibitor) arrests the proliferation of angiogenesis vessels while at the same time inducing the proliferation of more mature vessels which are less critical for efficient angiogenesis in the context of disease.
Rui Benedito explained that the arrest of angiogenesis is due to a bell-shaped dose-response to the mitogenic stimulation. At high levels of mitogenic stimulus, the endothelial cells migrate and branch, but do not proliferate. Eventually, this affects the sustainable development of the blood vessels and the growth or regeneration of the surrounding tissues.
It is possible the now discovered mechanism could also explain the failure of several clinical trials seeking to boost angiogenesis in ischemic hearts after myocardial infarction. The lead author of the study believed that the results significantly increase their understanding of the biology of blood vessels and will enable them to design better therapeutic strategies to induce efficient angiogenesis in injured or ischemic tissues.
