A murine model of hereditary hemorrhagic telangiectasia
Annie Bourdeau, … , Daniel J. Dumont, Michelle Letarte
Annie Bourdeau, … , Daniel J. Dumont, Michelle Letarte
Published November 15, 1999
Citation Information: J Clin Invest. 1999;104(10):1343-1351. https://doi.org/10.1172/JCI8088.
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Article

A murine model of hereditary hemorrhagic telangiectasia

Abstract

Endoglin (CD105), an accessory protein of the TGF-β receptor superfamily, is highly expressed on endothelial cells. Hereditary hemorrhagic telangiectasia type 1 (HHT1) is associated with mutations in the Endoglin gene, leading to haploinsufficiency. To generate a disease model and ascertain the role of endoglin in development, we generated mice lacking 1 or both copies of the gene. Endoglin null embryos die at gestational day 10.0–10.5 due to defects in vessel and heart development. Vessel formation appears normal until hemorrhage occurs in yolk sacs and embryos. The primitive vascular plexus of the yolk sac fails to mature into defined vessels, and vascular channels dilate and rupture. Internal bleeding is seen in the peritoneal cavity, implying fragile vessels. Heart development is arrested at day 9.0, and the atrioventricular canal endocardium fails to undergo mesenchymal transformation and cushion-tissue formation. These data suggest that endoglin is critical for both angiogenesis and heart valve formation. Some heterozygotes, either with an inbred 129/Ola or mixed C57BL/6-129/Ola background, show signs of HHT, such as telangiectases or recurrent nosebleeds. In this murine model of HHT, it appears that epigenetic factors and modifier genes, some of which are present in 129/Ola, contribute to disease heterogeneity.

Authors

Annie Bourdeau, Daniel J. Dumont, Michelle Letarte

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Vascular defects in End–/– mice. Whole-mount embryos in their yolk sacs ...
Vascular defects in End–/– mice. Whole-mount embryos in their yolk sacs were stained for β-gal activity. (a, b, e, and f) Direct microscopic examination of the yolk sacs. (c, d, g, and h) Sagittal histological sections. At E9.0, the normal capillary plexus and initiation of branching are seen in the End+/– embryo (a and c). The End–/– yolk sac also has a highly vascularized plexus, but no vessel branching is observed (b and d). At E9.5, a vitelline vessel (v) is readily detectable in the End+/– yolk sac (e); this intact vessel is full of primitive red cells (g). The End–/– yolk sac shows a disorganized capillary plexus and no vitelline vessels (f); abnormally dilated blood islands are seen (h), which have ruptured, releasing primitive erythroblasts toward the amnion (arrowhead). (i and j) Unstained E9.5 embryos, with yolk sac and placenta still attached. Bleeding in the yolk sac cavity (arrowhead) and edematous pericardium (arrow) are observed in End–/– embryo (j), compared with a littermate control (i). An unstained E9.0 End+/– embryo (k), dissected away from the yolk sac, is compared with an End–/– littermate (l), which shows internal bleeding (arrow). Sagittal sections stained for β-gal demonstrate the presence of blood (arrow) in the peritoneal cavity of the End–/– embryo (n), which is absent from the End+/– embryo (m). a, dorsal aorta; pc, peritoneal cavity; u, umbilical vein. Bar: 100 μm (a–h), 500 μm (i and j), 250 μm (k–n).