Copyright © 2005, European Society of Cardiology
Blood outgrowth endothelial cells from Hereditary Haemorrhagic Telangiectasia patients reveal abnormalities compatible with vascular lesions
aCentro de Investigaciones Biologicas, CSIC, Ramiro de Maeztu, 9. Madrid 28040, Spain
bDepartamento de Biología, Universidad Autónoma, Madrid, Spain
cDepartamento de Medicina Interna, Hospital Sierrallana, Torrelavega, Santander, Spain
dVascular Biology Centre, MMC 480,420, Delaware St, SE Minneapolis, MN 55455, USA
* Correspondence author. Tel.: +34 91 8373112x4246; fax: +34 91 5360432. Email address: bernabeu.c{at}cib.csic.es
Objective: Hereditary haemorrhagic telangiectasia (HHT) is originated by mutations in endoglin (HHT1) and ALK1 (HHT2) genes. The purpose of this work was to isolate and characterize circulating endothelial cells from HHT patients.
Methods: Pure primary cultures of blood outgrowth endothelial cells (BOECs) were obtained from 50 ml of peripheral blood by selection on collagen plates with endothelial medium.
Results: The amount of endoglin in HHT1–BOECs is half the controls, but HHT2–BOECs are also endoglin-deficient. Since the TGF-β/ALK1 pathway activates the endoglin promoter activity, these results suggest the involvement of ALK1 in endoglin gene expression. Endothelial TGF-β pathways, mediated by ALK1 and ALK5, are impaired in HHT cells. HHT–BOECs show disorganized and depolymerized actin fibers, as compared to the organized stress fibers of healthy–BOECs. Functionally, HHT–BOECs have impaired tube formation, in contrast with the cord-like structures derived from normal donors.
Conclusions: Decreased endoglin expression, impaired TGF-β signalling, disorganized cytoskeleton, and failure to form cord-like structures are common characteristics of endothelial cells from HHT patients. These features may lead to fragility of small vessels and bleeding characteristic of the HHT vascular dysplasia and to a disrupted and abnormal angiogenesis, which may explain the clinical symptoms associated with this disease.
KEYWORDS Endothelial receptors; Endothelial function; Signal transduction; Angiogenesis; Remodelling
1 These authors contributed equally to this work.
Time for primary review 14 days
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