Thresholds of Endoglin Expression in Endothelial Cells Explains Vascular Etiology in Hereditary Hemorrhagic Telangiectasia Type 1

International Journal of Molecular Sciences

Sabrina Martin¹  Sander van den Driesche²  Christine L. Mummery³  Kévin Montagne⁴  Hans-Jurgen J. Mager⁵  Franck Lebrin⁶  Jérémy H. Thalgott⁶  Georgios Galaris⁶  Ton J. Rabelink⁶  Geoffroy J. P. E. Goujon⁶ 

[1] Center for Interdisciplinary Research in Biology (CIRB), UMR7241/U1050, 75005 Paris, France;Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK;Department of Anatomy and Embryology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;Department of Mechanical Engineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8654, Japan;Department of Pulmonology, St Antonius Hospital, 3435 CM Nieuwegein, The Netherlands;Einthoven Laboratory for Experimental Vascular Medicine, Department of Internal Medicine (Nephrology), Leiden University Medical Center, 2333 ZA Leiden, The Netherlands;

关键词: endoglin;    hereditary hemorrhagic telangiectasia;    cell signaling;    endothelial cells;   

DOI  :  10.3390/ijms22168948

来源: DOAJ

【 摘 要 】

Hereditary Hemorrhagic Telangiectasia type 1 (HHT1) is an autosomal dominant inherited disease characterized by arteriovenous malformations and hemorrhage. HHT1 is caused by mutations in ENDOGLIN, which encodes an ancillary receptor for Transforming Growth Factor-β/Bone Morphogenetic Protein-9 expressed in all vascular endothelial cells. Haploinsufficiency is widely accepted as the underlying mechanism for HHT1. However, it remains intriguing that only some, but not all, vascular beds are affected, as these causal gene mutations are present in vasculature throughout the body. Here, we have examined the endoglin expression levels in the blood vessels of multiple organs in mice and in humans. We found a positive correlation between low basal levels of endoglin and the general prevalence of clinical manifestations in selected organs. Endoglin was found to be particularly low in the skin, the earliest site of vascular lesions in HHT1, and even undetectable in the arteries and capillaries of heterozygous endoglin mice. Endoglin levels did not appear to be associated with organ-specific vascular functions. Instead, our data revealed a critical endoglin threshold compatible with the haploinsufficiency model, below which endothelial cells independent of their tissue of origin exhibited abnormal responses to Vascular Endothelial Growth Factor. Our results support the development of drugs promoting endoglin expression as potentially protective.

【 授权许可】

Unknown