A mechanosensitive transcriptional mechanism that controls angiogenesis

Abstract

Angiogenesis is controlled by physical interactions between cells and extracellular matrix as well as soluble angiogenic factors, such as VEGF. However, the mechanism by which mechanical signals integrate with other microenvironmental cues to regulate neovascularization remains unknown. Here we show that the Rho inhibitor, p190RhoGAP (also known as GRLF1), controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between two antagonistic transcription factors, TFII-I (also known as GTF2I) and GATA2, that govern gene expression of the VEGF receptor VEGFR2 (also known as KDR). Moreover, this new angiogenesis signalling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. This is, to our knowledge, the first known functional cross-antagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.

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Figure 1: TFII-I and GATA2 control VEGFR2 expression via p190RhoGAP.
Figure 2: Matrix elasticity controls VEGFR2 expression via TFII-I and GATA2.
Figure 3: Antagonism between GATA2 and TFII-I controls capillary cell migration and tube formation in vitro.
Figure 4: Matrix elasticity controls vessel formation via TFII-I and GATA2 in vivo.
Figure 5: TFII-I, GATA2 and p190RhoGAP regulate retinal vessel formation in vivo.

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Acknowledgements

We thank T. Polte, E. Pravda, M. de Bruijn and K. Johnson for their technical suggestions and assistance, T. Nakano and H. Sabe for providing plasmids, the National Institutes of Health (NIH) for providing VEGF, and D. Weitz for providing assistance with rheometry measurements. This work was supported by funds from the NIH (to D.E.I., L.E.H.S. and K.M.C.), V. Kann Rasmussen Foundation (to L.E.H.S.), Children’s Hospital Mental Retardation and Developmental Disabilities Research Center (to L.E.H.S.), a Research to Prevent Blindness Lew Wasserman Merit Award (to L.E.H.S.), American Heart Association (to A.M.), and a Children’s Hospital House Officer Development Award (to A.M.); D.E.I. is a recipient of a DoD Breast Cancer Innovator Award.

Author Contributions A.M. conceived the experiments, performed experiments, designed research and analysed data with assistance from K.M.C., T.M., C.W.Y., D.H., C.M.A., G.M., L.E.H.S. and D.E.I. A.M. wrote the manuscript with D.E.I., with input from L.E.H.S.

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Correspondence to Donald E. Ingber.

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Mammoto, A., Connor, K., Mammoto, T. et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature 457, 1103–1108 (2009). https://doi.org/10.1038/nature07765

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