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First published online November 11, 2009
doi: 10.1242/10.1242/dev.035014

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Regulation of lymphatic-blood vessel separation by endothelial Rac1

Gabriela D'Amico^1,*,, Dylan T. Jones¹, Emma Nye², Karen Sapienza³, Antoine R. Ramjuan¹, Louise E. Reynolds¹, Stephen D. Robinson¹, Vassiliki Kostourou^1,8, Dolores Martinez⁴, Deborah Aubyn⁵, Richard Grose⁶, Gareth J. Thomas³, Bradley Spencer-Dene^2,9, Daniel Zicha⁵, Derek Davies⁴, Victor Tybulewicz⁷ and Kairbaan M. Hodivala-Dilke^1,

¹ Adhesion and Angiogenesis Laboratory, Institute of Cancer and Cancer Research UK, Bart's & The London Queen Mary's School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
² Experimental Histopathology Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
³ Centre for Tumour Biology, Institute of Cancer and Cancer Research UK, Bart's & The London Queen Mary's School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
⁴ Fluorescence Activated Cell Sorting Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
⁵ Light Microscopy Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London, WC2A 3PX, UK
⁶ Growth Factor Signalling Laboratory, Institute of Cancer and Cancer Research UK, Bart's & The London Queen Mary's School of Medicine & Dentistry, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK
⁷ Division of Immune Cell Biology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK
⁸ BSRC Alexander Fleming, 34 Fleming street, 166 72 Vari, Athens, Greece
⁹ Histopathology, Imperial College London, London, W12 0NN, UK

Authors for correspondence (Gabriela.Damico{at}Helsinki.FI; K.Hodivala-Dilke{at}qmul.ac.uk)

Accepted September 29, 2009

Sprouting angiogenesis and lymphatic-blood vessel segregation both involve the migration of endothelial cells, but the precise migratory molecules that govern the decision of blood vascular endothelial cells to segregate into lymphatic vasculature are unknown. Here, we deleted endothelial Rac1 in mice (Tie1-Cre⁺;Rac1^fl/fl) and revealed, unexpectedly, that whereas blood vessel morphology appeared normal, lymphatic-blood vessel separation was impaired, with corresponding edema, haemorrhage and embryonic lethality. Importantly, normal levels of Rac1 were essential for directed endothelial cell migratory responses to lymphatic-inductive signals. Our studies identify Rac1 as a crucial part of the migratory machinery required for endothelial cells to separate and form lymphatic vasculature.

Key words: Rac1 conditional knockout, Lymphangiogenesis, Vegfr3 (Flt4), Tie1-Cre, Blood-filled lymphatics

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