Clonal Expansion of Endothelial Cells Contributes to Ischemia-Induced Neovascularization
Rationale: Vascularization is critical to maintain organ function. Although many molecular pathways were shown to control vessel growth, the genuine process of capillary formation under different conditions is unclear.
Objective: Here, we elucidated whether clonal expansion contributes to vessel growth by using Confetti mice for genetic tracing of clonally expanding endothelial cells.
Methods and Results: In postnatal retina angiogenesis, we predominantly observed random distribution of fluorescence labeled endothelial cells indicative of random integration or cell mixing. However, in models of pathophysiological angiogenesis (retinopathy of prematurity), as well as ischemia-induced angiogenesis in limbs and hearts, clonally expanded endothelial cells were significantly more abundant (up to 69%). Inhibition of vascular endothelial growth factor receptor 2 reduced clonal expansion after ischemia. To determine the mechanism underlying clonal expansion in vivo, we assessed gene expression specifically in clonally expanded endothelial cells selected by laser capture microscopy. Clonally expanded endothelial cells showed an enrichment of genes involved in endothelial-to-mesenchymal transition (EndMT). Moreover, hypoxia induced clonal expansion and EndMT in endothelial cells in vitro suggesting that hypoxia-enhanced EndMT might contribute to vessel growth under ischemia.
Conclusions: Our data suggest that neovascularization after ischemia is partially mediated by clonal expansion of endothelial cells. Identification of the pathways that control clonal expansion may provide novel tools to augment therapeutic neovascularization or treat pathological angiogenesis.
- Clonal expansion
- cardiovascular disease
- acute myocardial infarction
- endothelial cell
- Received October 29, 2017.
- Revision received January 3, 2018.
- Accepted January 11, 2018.