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First published online 20 November 2007
doi: 10.1242/jcs.013169

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Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice

Rita L. C. Carvalho^1,*, Fumiko Itoh^2,*, Marie-Jose Goumans^3,, Franck Lebrin¹, Mitsuyasu Kato², Satoru Takahashi⁴, Masatsugu Ema⁴, Susumu Itoh², Marga van Rooijen¹, Philippe Bertolino³, Peter ten Dijke^3,5 and Christine L. Mummery^1,

¹ Hubrecht Laboratory, Netherlands Institute for Developmental Biology, Uppsalalaan 8, 3584CT Utrecht, The Netherlands
² Department of Experimental Pathology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
³ Division of Cellular Biochemistry, The Netherlands Cancer Institute, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands
⁴ Department of Anatomy and Embryology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575, Japan
⁵ Leiden University Medical Center, Department of Molecular Cell Biology, Leiden, The Netherlands

Author for correspondence (e-mail: c.mummery{at}niob.knaw.nl)

Accepted 28 August 2007

Vascular development depends on transforming growth factor β (TGFβ), but whether signalling of this protein is required for the development of endothelial cells (ECs), vascular smooth muscle cells (VSMCs) or both is unclear. To address this, we selectively deleted the type I (ALK5, TGFBR1) and type II (TβRII, TGFBR2) receptors in mice. Absence of either receptor in ECs resulted in vascular defects in the yolk sac, as seen in mice lacking receptors in all cells, causing embryonic lethality at embryonic day (E)10.5. Deletion of TβRII specifically in VSMCs also resulted in vascular defects in the yolk sac; however, these were observed at later stages of development, allowing the embryo to survive to E12.5. Because TGFβ can also signal in ECs via ALK1 (ACVRL1), we replaced ALK5 by a mutant defective in SMAD2 and SMAD3 (SMAD2/3) activation that retained the ability to transactivate ALK1. This again caused defects in the yolk sac vasculature with embryonic lethality at E10.5, demonstrating that TGFβ/ALK1 signalling in ECs cannot compensate for the lack of TGFβ/ALK5-induced SMAD2/3 signalling in vivo. Unexpectedly, SMAD2 phosphorylation and -smooth muscle actin (SMA, ACTA2) expression occurred in the yolk sacs of ALK5^–/– embryos and ALK5^–/– embryonic stem cells undergoing vasculogenesis, and these processes could be blocked by an ALK4 (ACVR1B)/ALK5 inhibitor. Together, the data show that ALK5 is required in ECs and VSMCs for yolk sac vasculogenesis; in the absence of ALK5, ALK4 mediates SMAD2 phosphorylation and consequently SMA expression.

Key words: TGFβ, ALK5, Endothelial cells

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