RhoB controls coordination of adult angiogenesis and lymphangiogenesis following injury by regulating VEZF1-mediated transcription

Damien Gerald (), Irit Adini, Sharon Shechter, Carole Perruzzi, Joseph Varnau, Benjamin Hopkins, Shiva Kazerounian, Peter Kurschat, Stephanie Blachon, Santosh Khedkar, Mandrita Bagchi, David Sherris, George C. Prendergast, Michael Klagsbrun, Heidi Stuhlmann, Alan C. Rigby, Janice A. Nagy and Laura E. Benjamin
Additional contact information
Damien Gerald: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Irit Adini: Children’s Hospital, Harvard Medical School
Sharon Shechter: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Carole Perruzzi: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Joseph Varnau: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Benjamin Hopkins: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Shiva Kazerounian: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Peter Kurschat: Children’s Hospital, Harvard Medical School
Stephanie Blachon: Hybrigenics Services
Santosh Khedkar: ImClone Systems (a wholly owned subsidiary of Eli Lilly and Company)
Mandrita Bagchi: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
David Sherris: VasculoMedics Inc.
George C. Prendergast: Anatomy and Cell Biology, Kimmel Cancer Center, Jefferson Medical School, Thomas Jefferson University
Michael Klagsbrun: Children’s Hospital, Harvard Medical School
Heidi Stuhlmann: Weill Cornell Medical College
Alan C. Rigby: ImClone Systems (a wholly owned subsidiary of Eli Lilly and Company)
Janice A. Nagy: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School
Laura E. Benjamin: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2013, vol. 4, issue 1, 1-15

Abstract: Abstract Mechanisms governing the distinct temporal dynamics that characterize post-natal angiogenesis and lymphangiogenesis elicited by cutaneous wounds and inflammation remain unclear. RhoB, a stress-induced small GTPase, modulates cellular responses to growth factors, genotoxic stress and neoplastic transformation. Here we show, using RhoB null mice, that loss of RhoB decreases pathological angiogenesis in the ischaemic retina and reduces angiogenesis in response to cutaneous wounding, but enhances lymphangiogenesis following both dermal wounding and inflammatory challenge. We link these unique and opposing roles of RhoB in blood versus lymphatic vasculatures to the RhoB-mediated differential regulation of sprouting and proliferation in primary human blood versus lymphatic endothelial cells. We demonstrate that nuclear RhoB-GTP controls expression of distinct gene sets in each endothelial lineage by regulating VEZF1-mediated transcription. Finally, we identify a small-molecule inhibitor of VEZF1–DNA interaction that recapitulates RhoB loss in ischaemic retinopathy. Our findings establish the first intra-endothelial molecular pathway governing the phased response of angiogenesis and lymphangiogenesis following injury.

Date: 2013
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DOI: 10.1038/ncomms3824

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