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(Circulation Research. 2004;94:542.)
© 2004 American Heart Association, Inc.

Integrative Physiology

Homocysteine Induces Endothelial Cell Detachment and Vessel Wall Thickening During Chick Embryonic Development

Marit J. Boot, Régine P.M. Steegers-Theunissen, Robert E. Poelmann, Liesbeth van Iperen, Adriana C. Gittenberger-de Groot

From the Department of Anatomy and Embryology (M.J.B., R.E.P., L.v.I., A.C.G.-d.G.), Leiden University Medical Center, Leiden, The Netherlands; Department of Epidemiology/Biostatistics (R.P.M.S.-T.), University Medical Center Nijmegen and Department of Obstetrics/Gynaecology (R.P.M.S.-T.), Erasmus Medical Center Rotterdam, The Netherlands.

Correspondence to Prof Dr A.C. Gittenberger-de Groot, Dept of Anatomy and Embryology, Leiden University Medical Center, PO Box 9602, 2300 RC Leiden, The Netherlands. E-mail A.C.Gittenberger-de_Groot{at}lumc.nl

Homocysteine affects the migration and differentiation of neural crest cells in vitro and can result in neural tube defects in vivo. Furthermore, homocysteine has been described as an important determinant in vascular disease in human adults. However, little is known about the effects of homocysteine on the development of embryonic vessels. In this study, we injected homocysteine (30 µmol/L) into the neural tube lumen of chick embryos at the time point of neural crest cell emigration, and analyzed the effects on the neural crest–derived pharyngeal arch arteries, like the brachiocephalic arteries, and the mesoderm-derived arteries, such as the dorsal aorta. By stage HH35, we observed detachment of the endothelium, decreased expression of the extracellular matrix proteins fibrillin-2, and fibronectin in the pharyngeal arch arteries, whereas the dorsal aorta was identical in homocysteine-neural tube–injected and control embryos. No effect of homocysteine on endothelin-1 mRNA expression was observed. By stage HH40, the brachiocephalic arteries of homocysteine-neural tube–injected embryos displayed a decreased lumen diameter, an increased intima- and media-thickness, and an increased number of actin layers compared with the brachiocephalic arteries in control embryos. We propose that homocysteine affects the neural crest–derived smooth muscle cells and their extracellular matrix proteins in the pharyngeal arch arteries, resulting in an abnormal smooth muscle to endothelial cell interaction, leading to endothelial cell detachment. We suggest that, as in adult life, increased homocysteine concentrations lead to vascular damage in the embryo. This prenatal damage might increase the susceptibility to develop vessel pathology later in life.

Key Words: neural crest • cardiovascular development • pharyngeal arch arteries • extracellular matrix proteins

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