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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.

Author information

1
From the Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany (Y.M., T.L., S.F.G., R.A.B., S.D.); Department of Cardiology, Internal Medicine III, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany (A.M.Z.); Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.G., T.B.); Department of Medicine, Hematology, and Oncology, Goethe University Frankfurt, Germany (L.D., M.A.R.); and Partner site Rhein/Main, German Center of Cardiovascular Research DZHK, Frankfurt (Y.M., T.L., S.F.G., T.B., A.M.Z., R.A.B., S.D.).
2
From the Institute for Cardiovascular Regeneration, Center of Molecular Medicine, Goethe University, Frankfurt, Germany (Y.M., T.L., S.F.G., R.A.B., S.D.); Department of Cardiology, Internal Medicine III, Johann Wolfgang Goethe University Hospital, Frankfurt, Germany (A.M.Z.); Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (S.G., T.B.); Department of Medicine, Hematology, and Oncology, Goethe University Frankfurt, Germany (L.D., M.A.R.); and Partner site Rhein/Main, German Center of Cardiovascular Research DZHK, Frankfurt (Y.M., T.L., S.F.G., T.B., A.M.Z., R.A.B., S.D.). dimmeler@em.uni-frankfurt.de.

Abstract

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 (ECs).

METHODS AND RESULTS:

In postnatal retina angiogenesis, we predominantly observed random distribution of fluorescence labeled ECs 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 ECs were significantly more abundant (≤69%). Inhibition of VEGFR2 (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 ECs selected by laser capture microscopy. Clonally expanded ECs showed an enrichment of genes involved in endothelial-to-mesenchymal transition. Moreover, hypoxia-induced clonal expansion and endothelial-to-mesenchymal transition in ECs in vitro suggesting that hypoxia-enhanced endothelial-to-mesenchymal transition might contribute to vessel growth under ischemia.

CONCLUSIONS:

Our data suggest that neovascularization after ischemia is partially mediated by clonal expansion of ECs. Identification of the pathways that control clonal expansion may provide novel tools to augment therapeutic neovascularization or treat pathological angiogenesis.

KEYWORDS:

cardiovascular diseases; endothelial cells; hypoxia; ischemia; mice

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