1. Vascular Biology Program, Departments of Pathology & Surgery,
2. Department of Ophthalmology, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
3. Department of Genetics, Harvard Medical School, Harvard Institute of Medicine, Boston, Massachusetts 02215, USA
4. Wyss Institute for Biologically Inspired Engineering and Harvard School of Engineering and Applied Sciences, Cambridge, Massachusetts 02138, USA
5. Present address: Department of Medicine, Boston University School of Medicine, Boston, Massachusetts 02118, USA.

Correspondence to: Donald E. Ingber^1,4 Correspondence and requests for materials should be addressed to D.E.I. (Email: donald.ingber@childrens.harvard.edu).

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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