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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Figure 6

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Microscopic examination of a telangiectasia from a 129/Ola End+/– mouse....
Microscopic examination of a telangiectasia from a 129/Ola End+/– mouse. Ear lobe biopsies from an End+/– mouse and normal littermate were left unstained (a and b) or were stained for β-gal activity (c and d). (a) A dilated vessel (arrow), engorged with blood, is seen in the affected End+/– ear lobe, together with a necrotic area (arrowhead) from a telangiectasia ruptured previously. (b) The corresponding area from a nonaffected control 129/Ola mouse shows much smaller vessels. (c) A small telangiectasia (arrow), close to the edge of the affected ear, appears as a dilated vessel distinct from the adjacent network of capillaries. (d) Normal capillary network from a nonaffected ear. (e) A cross-section of the resected ear segment from the affected 129/Ola End+/– mouse was stained for β-gal. An enlarged vessel filled with blood (arrow), corresponding to a telangiectasia, is seen. The endothelial cells of this vessel and of several normal small capillaries are stained; a layer of cartilage (ca) is seen across the section. Bar: 500 μm (a–d) and 100 μm (e).