A recent study reveals a new cellular and molecular mechanism essential for the process of arterialization—the development of arteries from blood capillaries. Activation of this mechanism could improve the recovery of heart function after transient or long-term reduction in heart blood flow.
The research, done by a group at the Centro Nacional de Investigaciones Cardiovasculares (CNIC) in Madrid, Spain, not only advances understanding of the biology of blood vessels, but also points the way to the design of new therapeutic strategies to induce vascularization and more effective blood perfusion of injured or ischemic tissues.
The work is published in Nature, in the article, “Arterialization requires the timely suppression of cell growth.”
Until now, vascular arterialization was believed to depend on the differentiation and specification of a progenitor cell into an arterial cell, a process thought to require transcriptional activation and DNA remodeling. The new discovery shows that arterialization involves instead the timely suppression of metabolism and the cell cycle and that this event is both necessary and sufficient to trigger the differentiation and development of arteries.
In the past 20 years, scientists have discovered several cellular and molecular mechanisms that are essential for the formation and differentiation of arteries and veins. The first blood vessels to develop in any growing organ are immature and form an undifferentiated and rudimentary vascular network called a precursor vascular plexus. This network is formed from endothelial cells and is relatively inefficient at transporting blood. It can be likened to a road network built for local traffic but lacking a system of larger connecting highways.
The formation of a hierarchical vascular system composed of larger conduction arteries and veins is therefore essential for the efficient transport of blood to and from tissues. “The incorrect development of this system causes premature embryonic death or potentially fatal diseases linked to vascular malformations that can cause stroke, poor oxygen supply, or inadequate tissue perfusion,” explained the study authors.
Arterialization is thought to occur by the induction of a highly conserved arterial genetic program in a subset of vessels that will later form arteries. The initial steps of arterial specification require both the VEGF and Notch signaling pathways. “Notch is a molecular signaling pathway that directly regulates the transcription of an immense array of genes that alter a cell’s biology. When Notch is not activated in endothelial cells, arterial specification and development fails, remaining only capillary and venous endothelial cells,” said Rui Benedito, PhD, group leader, CNIC.
This led to the view that arteries are built through the induction of a highly conserved, Notch-dependent program of genetic change in a subset of endothelial cells. This genetic program was thought to be essential for the capacity of endothelial cells to differentiate, migrate, and form arteries.
Using sophisticated mouse models, cell imaging, and fate mapping tools, Benedito’s lab has now discovered that cells with distinct Notch signaling levels are biased towards a particular fate, but not genetically pre-determined, as they can adopt distinct arteriovenous fates if placed in the appropriate biophysical context.
The group combined inducible genetic mosaics and transcriptomics to modulate and define the function of these signaling pathways in cell proliferation, arteriovenous differentiation, and mobilization.
Wen Luo, PhD, a postdoc in the Benedito lab, found that the main function of VEGF and Notch in arterializing endothelial cells is to inhibit Myc, suppressing its ability to promote cell proliferation and metabolism. The study shows that Myc inhibition is necessary and sufficient to induce an effective bias towards arterialization.
The work led the authors to suggest a new model. Benedito proposed that “Notch–RBPJ suppresses MYC-dependent cell cycle or biosynthetic activity, rendering ECs more permissive to the adoption of an arterial phenotype without the need for Notch-dependent genetic pre-determination or differentiation.”
The results also have important implications for the use of drugs to boost angiogenesis in ischemic cardiovascular disease. The study suggests that pro-angiogenic drugs that stimulate general blood vessel proliferation will suppress arterialization. “One of our future goals will be to identify new ways to suppress proliferation signals exclusively in pre-arterial cells, thereby promoting effective arterialization without negatively interfering with the induction of capillary angiogenesis” said Benedito.
From a translational standpoint, the authors concluded that the ability to modulate arterial or venous identity of blood vessels is of great interest for the treatment of coronary artery disease and myocardial infarction. The results obtained could lead to novel therapeutic approaches to induce effective arterialization in ischemic cardiovascular disease.