Abstract
Endothelial cells form a critical component of the coronary vasculature, yet the factors regulating their development remain poorly defined. Here we reveal a novel role for the transmembrane protein CRIM1 in mediating cardiac endothelial cell development. In the absence of Crim1 in vivo, the coronary vasculature is malformed, the number of endothelial cells reduced, and the canonical BMP pathway dysregulated. Moreover, we reveal that CRIM1 can bind IGFs, and regulate IGF signalling within endothelial cells. Finally, loss of CRIM1 from human cardiac endothelial cells results in misregulation of endothelial genes, predicted by pathway analysis to be involved in an increased inflammatory response and cytolysis, reminiscent of endothelial cell dysfunction in cardiovascular disease pathogenesis. Collectively, these findings implicate CRIM1 in endothelial cell development and homeostasis in the coronary vasculature.
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Acknowledgements
We are grateful to Prof. Melissa Little and Prof. Nadia Rosenthal for providing us with the CRIM1 and IGF-1 Ea/Eb expression constructs, respectively. Tie2-Cre mice were a kind gift from Prof. Richard Harvey at the Victor Chang Cardiac Research Institute. This work was funded by grants from the National Health and Medical Research Council to MP (1057751) and DJP (631658), and an ARC Discovery Project to MP (DP160100368). MP holds an Australian Research Council Future Fellowship (FT120100170). SI was supported by a UQ Research Scholarship. Performed experiments: SI, YC, TJH. Analysed data: SI, MP, DJP. Wrote paper: SI, MP. Edited paper: SI, WGT, AGS, MP, DJP.
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David J. Pennisi and Michael Piper authors contributed equally to this work.
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Iyer, S., Chhabra, Y., Harvey, T.J. et al. CRIM1 is necessary for coronary vascular endothelial cell development and homeostasis. J Mol Hist 48, 53–61 (2017). https://doi.org/10.1007/s10735-016-9702-3
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DOI: https://doi.org/10.1007/s10735-016-9702-3