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. Access through your institution Buy or subscribe This is a preview of subscription content, access via

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Scholar  Download references 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. AUTHOR INFORMATION Author notes * Gustavo Mostoslavsky Present address:

Present address: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA., AUTHORS AND AFFILIATIONS * Departments of Pathology & Surgery,, Vascular

Biology Program, Akiko Mammoto, Tadanori Mammoto, Chong Wing Yung, Dongeun Huh & Donald E. Ingber * Department of Ophthalmology, Children’s Hospital and Harvard Medical School, Boston,

Massachusetts 02115, USA, Kip M. Connor, Christopher M. Aderman & Lois E. H. Smith * Department of Genetics, Harvard Medical School, Harvard Institute of Medicine, Boston, Massachusetts

02215, USA, Gustavo Mostoslavsky * Wyss Institute for Biologically Inspired Engineering and Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts 02138, USA , Donald

E. Ingber Authors * Akiko Mammoto View author publications You can also search for this author inPubMed Google Scholar * Kip M. Connor View author publications You can also search for this

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Scholar CORRESPONDING AUTHOR Correspondence to Donald E. Ingber. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Figures S1-S13 with Legends and

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SLIDE FOR FIG. 5 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 02 October 2008 * Accepted: 31 December 2008 * Issue

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