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Clonal expansion of endothelial cells contributes to blood vessel growth

January 2018. The circulatory system is essential to maintain organ function by providing oxygen and nutrients. The turn-over of the adult 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 remains unclear.

In a new study, scientists from the Goethe University Frankfurt and the Max Plank Institute for Heart and Lung Research examined whether clonal expansion of mature endothelial cells contributes to vessel growth by using Confetti mice for genetic tracing. Analyses of clonal expansion in postnatal retina angiogenesis suggested that the majority of the newly formed vessels were not derived from clonally expanding cells, but rather by random integration or cell mixing. Under pathophysiological angiogenesis (retinopathy of prematurity), as well as ischemia-induced angiogenesis in limbs and hearts, clonally expanded VE-cadherin+ cell-derived endothelial cells were significantly more abundant. Inhibition of vascular endothelial growth factor receptor 2 reduced clonal expansion after ischemia.

To determine the mechanism underlying clonal expansion in vivo, the scientists assessed gene expression specifically in clonally expanded endothelial cells selected by laser capture microscopy. These cells showed an enrichment of genes involved in endothelial-to-mesenchymal transition (EndMT). Hypoxia induced clonal expansion and EndMT in endothelial cells in vitro suggesting that hypoxia-enhanced EndMT might contribute to vessel growth under ischemia. Identification of the pathways that control clonal expansion may provide novel tools to augment therapeutic neovascularization or treat pathological angiogenesis.

Stefanie Dimmeler, Institute of Cardiovascular Regeneration, Goethe University Frankfurt, Germany, dimmeler@em.uni-frankfurt.de, www.cardiovascular-regeneration.com 


Manavski Y, Lucas T, Glaser SF, Dorsheimer L, G√ľnther S, Braun T, Rieger MA, Zeiher AM, Boon RA, Dimmeler S (2018) Clonal expansion of endothelial cells contributes to ischemia-induced neovascularization. Circulation Research, published online 22 January 2018. http://dx.doi.org/10.1161/circresaha.117.312310