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Cardiovascular Research 2006 69(4):845-854; doi:10.1016/j.cardiores.2005.11.020
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Copyright © 2005, European Society of Cardiology

Reduced angiogenic responses in adult endoglin heterozygous mice

Mirjana Jerkica,b,1, Alicia Rodríguez-Barberoa,1, Marta Prietoa, Mourad Toporsianb,d, Miguel Pericachoa, Juan V. Rivas-Elenaa, Juana Obreoa, Angela Wangb, Fernando Pérez-Barriocanala, Miguel Arévaloc, Carmelo Bernabéue, Michelle Letarteb,d and José M. López-Novoaa,*

aInstituto "Reina Sofía" de Investigación Nefrológica, Departamento de Fisiología y Farmacología, Universidad de Salamanca, Salamanca, Edificio Departamental, Campus Miguel de Unamuno, 37007 Salamanca, Spain
bCancer Research Program, The Hospital for Sick Children, Toronto, Canada M5G1X8
cDepartmento de Anatomía e Histología Humanas, Universidad de Salamanca, Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain
dThe Heart and Stroke Lewar Centre of Excellence, University of Toronto, Toronto, Canada
eCentro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Ramiro de Maeztu, 9, 28040 Madrid, Spain

* Corresponding author. Tel.: +34 923 294 472; fax: +34 923 294 669. Email address: jmlnovoa{at}usal.es

Objective: To determine if angiogenesis is altered in adult Endoglin heterozygous (Eng+/–) mice, the animal model for the vascular disorder hereditary hemorrhagic telangiectasia type 1 (HHT1).

Methods: Primary cultures of endothelial cells were generated from Eng+/– and Eng+/+ mice and analyzed for proliferation, migration, and ability to form capillary-like tubes. Endothelial cells derived from umbilical veins of newborns (HUVEC) with an HHT1 genotype were also tested for capillary formation. Two in vivo models of angiogenesis were tested in the Eng+/– and Eng+/+ mice: Matrigel implant-dependent angiogenesis and reperfusion following hindlimb ischemia.

Results: The Eng+/– endothelial cells displayed significantly reduced proliferation and migration, increased collagen production, and decreased NO synthase expression and vascular endothelial growth factor (VEGF) secretion. They also showed impaired capillary tube formation in vitro, as did the HHT1 HUVEC. These endothelial cell-specific abnormalities were associated with impaired Matrigel-dependent capillary tube formation in vivo and delayed reperfusion following hindlimb ischemia.

Conclusions: Although vascular development is normal in Eng+/– mice, angiogenic abnormalities were observed in the adult mice and their isolated endothelial cells. These results suggest that a normal level of endoglin is required for full angiogenic activity.

KEYWORDS Angiogenesis; Endoglin; HHT1; Nitric oxide; VEGF

1 These authors contributed equally to the paper.

Time for primary review 21 days


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