Defects in aortic fusion and craniofacial vasculature in the holoprosencephalic mouse embryo under inhibition of sonic hedgehog signaling.
Sonic hedgehog (Shh) is a well-known morphogen indispensable in facial and nervous development, and recently it has also garnered much attention as a potent angiogenic factor. We previously created an animal model of holoprosencephaly by administration of cyclopamine, a specific inhibitor of hedgehog signaling, to the mouse embryos cultured in vitro, and found several types of angiogenic defects. In this study, we focused on other angiogenic phenotypes in the same model. When cyclopamine was added for embryonic day (E) 8.0-9.5, a pair of immature dorsal aortae, which normally fuse to form the single aorta by E9.5, remained to be separated. Expressions of vascular endothelial growth factor and bone morphogenetic protein 4, putative mediators of aortic fusion, were also reduced around the aorta by blockade of Shh signaling. When cyclopamine was added for E8.5-10.5, vessels on the surface of craniofacial region (possibly external cardinal veins) were extended and malformed. These results suggest that Shh signaling is essential for some aspects of embryonic angiogenesis, and that pathophysiology of holoprosencephaly may involve, at least in part, the Shh-dependent angiogenesis.
Nagase
Takashi
T
Clinical Research Center, National Hospital Organization Murayama Medical Center, 2-37-1 Gakuen, Musashimurayama-City, Tokyo 208-0011, Japan. nagase-t@murayama-crc.jp
Nagase
Miki
M
Yoshimura
Kotaro
K
Machida
Masafumi
M
Yamagishi
Masaaki
M
D000818:Animals; D001011:Aorta / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology; D001808:Blood Vessels / Q000002:abnormalities* / Q000187:drug effects / Q000196:embryology; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D046149:Embryo Culture Techniques; D005145:Face / Q000098:blood supply*; D005865:Gestational Age; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D016142:Holoprosencephaly / Q000139:chemically induced / Q000196:embryology*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D012886:Skull / Q000098:blood supply*; D013723:Teratogens / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors; D014704:Veratrum Alkaloids / Q000494:pharmacology
C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; C465570:Shh protein, mouse; D013723:Teratogens; D042461:Vascular Endothelial Growth Factor A; D014704:Veratrum Alkaloids; C000541:cyclopamine