Endoglin, an Ancillary TGFβ Receptor, Is Required for Extraembryonic Angiogenesis and Plays a Key Role in Heart Development

Abstract

Endoglin (CD105) is expressed on the surface of endothelial and haematopoietic cells in mammals and binds TGFbeta isoforms 1 and 3 in combination with the signaling complex of TGFbeta receptors types I and II. Endoglin expression increases during angiogenesis, wound healing, and inflammation, all of which are associated with TGFbeta signaling and alterations in vascular structure. The importance of endoglin for normal vascular architecture is further indicated by the association of mutations in the endoglin gene with the inherited disorder Hereditary Haemorrhagic Telangiectasia Type 1 (HHT1), a disease characterised by bleeding from vascular malformations. In order to study the role of endoglin in vivo in more detail and to work toward developing an animal model of HHT1, we have derived mice that carry a targeted nonsense mutation in the endoglin gene. Studies on these mice have revealed that endoglin is essential for early development. Embryos homozygous for the endoglin mutation fail to progress beyond 10.5 days postcoitum and fail to form mature blood vessels in the yolk sac. This phenotype is remarkably similar to that of the TGFbeta1 and the TGFbeta receptor II knockout mice, indicating that endoglin is needed in vivo for TGFbeta1 signaling during extraembryonic vascular development. In addition, we have observed cardiac defects in homozygous endoglin-deficient embryos, suggesting endoglin also plays a role in cardiogenesis. We anticipate that heterozygous mice will ultimately serve as a useful disease model for HHT1, as some individuals have dilated and fragile blood vessels similar to vascular malformations seen in HHT patients.

MAP3Ks as central regulators of cell fate during development

“…They also exhibit extreme dilation and decreased complexity of vascular branching in the yolk sack as well as an absence of vascular smooth muscle (Jadrich et al, 2006). Interestingly, loss-of-function mutations in the TGF␤ type I receptor Alk1 and the auxiliary TGF␤ receptor endoglin display defects in vascular development that are similar to those observed in TAK1 null mice (Arthur et al, 2000;Urness et al, 2000). These findings, together with studies showing that TAK1 is activated by TGF␤ (Yamaguchi et al, 1995) indicate that TAK1 may be a major downstream effector of TGF␤ signals to regulate vascular development.…”

The TGFβ type II receptor plays a critical role in the endothelial cells during cardiac development

“…For morphological analysis, transverse sections that had been carefully matched for stage and position within the heart were stained with haematoxylin and eosin. For XGal staining, tissues were fixed for 30 min in 0.2% gluteraldehyde, 0.1M Phosphate Buffer, pH 7.2, 5 mM EGTA, 2 mM MgCl 2 , and 0.02% NP40 and then processed for XGal staining, paraffin sections, and eosin counterstaining as previously described (Arthur et al, 2000). All sections were mounted onto slides with histomount and photographed using a digital camera attached to a Zeiss Axioplan microscope.…”

Multiple growth factors regulate coronary embryonic vasculogenesis

“…However, the role of TGF-␤ 1 in vasculogenesis/angiogenesis is controversial, since this growth factor has been found to induce VEGF expression (Li et al, 1997;Seko et al, 1999;Zheng et al, 1999). Moreover, endoglin, a receptor for TGF-␤ isoforms 1 and 3, is essential for embryonic development of blood vessels (Arthur et al, 2000).…”