TCM Vol. 12, No. 7, 2002 299 Heather C. Etchevers, Gérard Couly, and Nicole M. Le Douarin are at the Institute of Cellular and Molecular Embryology, College of France, Nogent-sur-Marne, France. * Address correspondence to: Nicole M. Le Douarin, Institut d’Embryologie Cellulaire et Moléculaire du CNRS et du Collège de France, 49 bis avenue de la Belle Gabrielle, 94736 Nogent-sur-Marne Cedex, France. Tel.: (+33) 1-45-14-15-15; fax: (+33) 1-48-73-43-77; e-mail: nicole.le-douarin@college-de-france.fr. © 2002, Elsevier Science Inc. All rights reserved. 1050-1738/02/$-see front matter Morphogenesis of the Branchial Vascular Sector Heather C. Etchevers, Gérard Couly, and Nicole M. Le Douarin* The branchial and dorsal cephalic vascular sectors correspond to the blood vessels contained within evolutionarily recent and ancestral parts of the head, respectively. Recent work demonstrates that neural crest cells (NCCs) provide the pericytes, and connective and smooth muscle cells to the entire branchial sector in an ordered fashion. Initial NCC position is transposed to the vascular distal-to-proximal axis, explaining why circumscribed cephalic vascular anomalies are often associated with reproducible malformations in head tissues derived from the neural crest. Unlike the rest of the central nervous system, the forebrain requires mesenchyme-containing vascular-competent NCCs to survive during embryogenesis and beyond. (Trends Cardiovasc Med 2002;12:299–304). © 2002, Elsevier Science Inc. vides a cul-de-sac—the head fold—in which the brain, skull, mouth, cephalic muscles, and their blood vessels will later develop. Experimental embryology has discovered many of the mechanisms by which developing cephalic tissues contact each other and differentiate ap- propriately to their local environment. One major technique, the construction of quail-chick chimeras, exploits species differences in nuclear structure to per- manently mark cells grafted from a do- nor to a host embryo (Le Douarin 1969). By following the fate of grafted cells at later time points, it was shown that the mesoderm lateral to the neural plate of the future brain gives rise to both stri- ated muscles and the endothelium of all cephalic blood vessels. According to the anteroposterior level at which a given graft was performed, a corresponding segment of the cephalic and encephalic vasculature contained endothelial cells of graft origin, whereas the nearby mus- cles also contained grafted cells (Couly et al. 1992 and 1995). The endothelial cell lineage becomes distinct from other future mesodermal progeny at a very early time point, when the future head is barely distinguished by an anterior trans- verse buckling in the germ layers. A ty- rosine kinase receptor to the vascular endothelium growth factor, known as VEGFR2, is already expressed at this time point in a subset of cephalic meso- dermal cells that subsequently acquire characteristics of endothelial cells (Eich- mann et al. 1993). Neural crest cells (NCCs) also con- tribute to much of the cephalic vascula- ture, but never to blood vessels in the body. NCCs delaminate from the bound- aries between the ectoderm and the me- dian neural plate as the latter forms the tube that will give rise to the central ner- vous system. They remain mesenchymal during their ventral migration toward the gut and their dorsolateral migration under the ectoderm. After colonizing the appropriate location, NCCs differentiate into the peripheral nervous system, certain types of endocrine cells, and all pigment cells aside from the retinal pigmented epithelium (reviewed in Le Douarin and Kalcheim 1999). Specifically in the head, NCCs also give rise to the “mesectoderm,” tissues that, in the body, are mesodermally derived. These include the intercalating connective components of the cephalic glands, muscles, and tendons. The dermis and adipose tissue overlying the jawed facial skeleton and brain case, the bones of that part of the skull, and certain re- gions of the meninges underlying it are also mesectodermal (Couly et al. 1993 and 1996, Köntges and Lumsden 1996, Le Lièvre 1974, Le Lièvre and Le Douarin 1975, Noden 1983). Early indications of the role of NCCs in cephalic blood vessels came from fate- mapping experiments that showed their constitution of the branchial arch mes- enchyme and subsequent incorporation into the smooth muscle walls of the cor- responding large arteries (Johnston 1966, Le Lièvre and Le Douarin 1975). In par- ticular, NCCs derived from the posterior rhombencephalon contribute all compo- nents of the proximal large arteries to the heart, with the exception of the endothe- lium (Le Lièvre and Le Douarin 1975). NCCs of this origin also play an impor- tant role in the septation of the pulmo- nary trunk from the aorta (Nishibatake et al. 1987, Waldo and Kirby 1993, Waldo et al. 1998). Although many of these experiments have been performed in the avian embryo, data from rodents confirm that NCCs are equally impor- tant to cephalic and outflow tract forma- tion in mammals (Imai et al. 1996, Jiang et al. 2000). Vascular anatomy is determined by to- pology. The adult head presents a partic- ularly complex three-dimensional struc- ture, with heavy localized demands for oxygenation and nutrition within the brain. Despite this complexity, underly- ing structural principles of cephalic blood vessel circuitry become apparent after examining the developing embryo. • Cephalic Blood Vessels Have Different Origins According to Their Position The vertebrate head starts out as a su- perposition of three cellular sheets: the endoderm, mesoderm, and ectoderm. Deformation of these germ layers around the anterior end of the notochord pro-