Published Online
on November 6, 2006

A more recent version of this article appeared on November 21, 2006

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Submitted on October 24, 2005
Revised on September 13, 2006
Accepted on September 15, 2006

Endoglin Has a Crucial Role in Blood Cell-Mediated Vascular Repair

Linda W. van Laake MD, Sander van den Driesche PhD, Simone Post MD, Alie Feijen MS, Maurits A. Jansen PhD, Mariette H. Driessens PhD, Johannes J. Mager MD, Repke J. Snijder MD, Cornelius J.J. Westermann MD, PhD, Pieter A. Doevendans MD, PhD, Cees J.A. van Echteld PhD, Peter ten Dijke PhD, Helen M. Arthur PhD, Marie-José Goumans PhD, Franck Lebrin PhD, and Christine L. Mummery PhD^*

From Hubrecht Laboratory (S.v.d.D., L.W.v.L., A.F., M.H.D., F.L., C.L.M.), Utrecht, the Netherlands; Laboratory of Experimental Cardiology, Department of Cardiology (L.W.v.L., S.P., P.A.D., M.J.G.) and NMR Laboratory (M.A.J., C.J.A.v.E.), Heart Lung Center, Utrecht, the Netherlands; St Antonius Hospital, Department of Pulmonary Disease (J.J.M., R.J.S., C.J.J.W.), Nieuwegein, the Netherlands; Leiden University Medical Center, Department of Molecular Cell Biology (P.t.D.), Leiden, the Netherlands; Institute of Human Genetics, International Centre for Life, University of Newcastle (H.M.A.), Newcastle Upon Tyne, UK; Interuniversity Cardiology Institute of the Netherlands (S.P., M.A.J., P.A.D., C.L.M.), Utrecht, the Netherlands; and INSERM Unit 525, Faculté de Médecine, Hôpital Pitié-Salpêtrière (F.L.), Paris, France.

^* To whom correspondence should be addressed. E-mail: franck.lebrin{at}chups.jussieu.fr)..

Background--Endoglin, an accessory receptor for transforming growth factor- in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity.

Methods and Results--In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng^+/-) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function in Eng^+/- mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients.

Conclusions--These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.

Key words: angiogenesis • genetics • magnetic resonance imaging • myocardial infarction • vessels

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