Research of the Month

April 2018

Circ Res. 2018 Mar 2;122(5):670-677. doi: 10.1161/CIRCRESAHA.117.312310. Epub 2018 Jan 22

Clonal Expansion of Endothelial Cells Contributes to Ischemia-Induced Neovascularization

Manavski Y, Lucas T, Glaser SF, Dorsheimer L, Gunther S, Braun T, Rieger MA, Zeiher AM, Boon RA and Dimmeler S

The circulatory system is essential to maintain organ function by providing oxygen and nutrients. In adults, the turnover of vasculature in most organs is considered to be low, but new blood vessels are formed after ischemia to provide oxygen to the ischemic tissues. Although many molecular pathways were shown to control vessel growth, the genuine process of capillary formation under different conditions is not fully understood.

Using genetic tracing of endothelial cells (so called “Confetti” mice model), the ECCPS investigators Dr. Manavski and Prof. Dr. Dimmeler now showed that single endothelial cells can clonally expand in tissue areas after exposure to ischemia. Interestingly, clonal expansion was only seen under stress conditions, whereas in postnatal retina angiogenesis endothelial cells showed a random integration or cell mixing. Inhibition of VEGFR2 (vascular endothelial growth factor receptor 2) reduced clonal expansion after ischemia. Using laser microdissection microscopy in vivo they authors further found that clonally expanded ECs showed an enrichment of genes involved in phenotypical changes of an endothelial to a mesenchymal signature, a process named “Endothelial-to-mesenchymal transition”. Although previous studies suggested that that the switch of an endothelial cells to a mesenchymal phenotype may be associated with an impaired capillary function and the development of tissue fibrosis, the newly formed vessels were perfused and appear functional. These data suggest that a transient incomplete mesenchymal transition may be required for the onset of vessel growth after ischemia. The study provide fundamental new insights into the process of vessel growth in the context of disease and may open novel therapeutic interventions e.g. by influencing clonal expansion.



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