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JCS ePress online publication date 20 Nov 2007
doi: 10.1242/jcs.013169

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Research Article

Compensatory signalling induced in the yolk sac vasculature by deletion of TGF{beta} receptors in mice


Rita L.C. Carvalho, Fumiko Itoh, Marie-Jose Goumans, Franck Lebrin, Mitsuyasu Kato, Satoru Takahashi, Masatsugu Ema, Susumu Itoh, Marga van Rooijen, Philippe Bertolino, Peter ten Dijke, and Christine L. Mummery*
* Author for correspondence (e-mail: c.mummery{at}niob.knaw.nl)

Vascular development depends on transforming growth factor {beta} (TGF{beta}), 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 (T{beta}RII, 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 T{beta}RII 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 TGF{beta} 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 TGF{beta}/ALK1 signalling in ECs cannot compensate for the lack of TGF{beta}/ALK5-induced SMAD2/3 signalling in vivo. Unexpectedly, SMAD2 phosphorylation and {alpha}-smooth muscle actin (SMA{alpha}, 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{alpha} expression.


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