CNIC scientists discovered a system in mice that promotes arterialization and perfusion in tissues with reduced blood flow.The research was published in naturalIt is proposed that selective blocking of cell proliferation and metabolism can improve the therapeutic angiogenesis of cardiovascular diseases.
Scientists from the National Center for Cardiovascular Research conducted a survey (China Internet Network Information Center), led by Rui Benedito, Has taken a big step in understanding biology Blood vessel.In addition, the results will allow the design of better treatment strategies to induce Vascularization And in the injured or ischemic tissue for more effective perfusion.
The research was published in natural, Describes a new cellular and molecular mechanism that is essential for the development of arteries from capillaries. This biological process is called Arterialization.Activate the system in organizations that have temporarily or permanently reduced the organization Blood flow -happened at Myocardial infarction-It can improve the regeneration and function of heart tissue.
So far, it has been believed that the arterialization process depends on the differentiation and characteristics of progenitor cells into arterial cells, and this process occurs through transcriptional activation and remodeling. ADN.But this work shows that it needs to suppress metabolism And cell cycle progression, which is a necessary event to trigger proper arterial development and differentiation.
In the past 20 years, scientists have discovered different cellular and molecular mechanisms that are critical to the formation and differentiation of molecules. artery with pulse. CNIC experts explained: “The first blood vessels that initially developed in any growth organ were immature and formed an undifferentiated and basic blood vessel network.”
The precursor blood vessel network or cluster is composed of endothelial cells and is relatively inefficient in transporting blood.However, due to the synergy of several genetic pathways-including Receptor gap And from Vascular endothelial growth factor (VEGF)-Initiate the differentiation and mobilization of cell subsets in these basic blood vessels to form future arteries and veins.
The author explained that the formation of a graded vascular system composed of larger conductive blood vessels is essential to efficiently transport blood into and out of tissues.
They said: “The failure of the system is due to premature embryo death or various life-threatening diseases due to vascular malformations that may lead to stroke, reduced oxygen supply or poor tissue perfusion.”
An image of a mouse heart that induces a multispectral genetic mosaic in the coronary vessels. This new genetic and imaging technology is used to induce different genetic mutations and to label individual coronary artery endothelial cells to map their fate during vascular development. These mutations inhibit or promote the development of the cell cycle, thereby determining the fate of its arteries or veins. Cells need to exit the cell cycle (G0) to form arteries. / CNIC
Effect on blood vessel formation
In order to start correct arterial regulation, two events must first occur: VEGF activation and Notch signaling pathway. “Notch is a cell signaling system that can directly regulate the transcription of a large number of genes that will change cell biology. Benedito explained that if this pathway is not activated in endothelial cells, the size and development of arteries will fail, so they can only form Capillary and venous endothelial cells.
This led to the idea that arteries are constructed by inducing a highly conservative and Notch-dependent arterial genetic alteration program in a subset of endothelial cells. This genetic program is believed to be essential for endothelial cell differentiation, migration and formation of arteries.
Due to the use of genetic models of imaging mice and cell mapping (fate mapping), Benedito’s research team found that cells with different Notch signal levels are biased, but not genetically predetermined, because if they are found, they can use different The arteriovenous destination. Appropriate biophysical environment.
Wen LuoThe first author of the study found that the main function of VEGF and Notch in vascular endothelial cells is to inhibit Myc and its role in promoting cell cycle and metabolism, and this inhibition alone can induce effective bias in arterialization.
This result has important implications for the use of pharmacological compounds aimed at stimulating liver cancer. Angiogenesis -Angiogenesis-in ischemic cardiovascular disease.
Therefore, this study shows that pro-angiogenic drugs that stimulate the general proliferation of blood vessels inhibit arterialization. Benedito added: “The key now is to find new ways to specifically eliminate the proliferation signals in the anterior artery cells, thereby inducing effective arterialization and promoting capillary angiogenesis.”
Researchers say that the ability to regulate the arterial or venous identity of blood vessels is of great interest to the treatment of coronary artery disease and myocardial ischemia. “The results obtained may better induce arterialization during tissue growth or regeneration or during blood vessel formation. Ischemic Cardiovascular Disease“, they came to a conclusion.
Luo Wen (Ren Benedito) and others: Arterialization requires timely suppression of cell growth. natural doi: 10.1038 / s41586-020-3018-x
The research has been funded by the European Research Council (ERC), which is 880 Grant AngioGenesHD (638028).