Regulation of vasculogenesis and angiogenesis by EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells.
Although the cellular and molecular mechanisms governing angiogenesis are only beginning to be understood, signaling through endothelial-restricted receptors, particularly receptor tyrosine kinases, has been shown to play a pivotal role in these events. Recent reports show that EphB receptor tyrosine kinases and their transmembrane-type ephrin-B2 ligands play essential roles in the embryonic vasculature. These studies suggest that cell-to-cell repellent effects due to bidirectional EphB/ephrin-B2 signaling may be crucial for vascular development, similar to the mechanism described for neuronal development. To test this hypothesis, we disrupted the precise expression pattern of EphB/ephrin-B2 in vivo by generating transgenic (CAGp-ephrin-B2 Tg) mice that express ephrin-B2 under the control of a ubiquitous and constitutive promoter, CMV enhancer-beta-actin promoter-beta-globin splicing acceptor (CAG). These mice displayed an abnormal segmental arrangement of intersomitic vessels, while such anomalies were not observed in Tie-2p-ephrin-B2 Tg mice in which ephrin-B2 was overexpressed in only vascular endothelial cells (ECs). This finding suggests that non-ECs expressing ephrin-B2 alter the migration of ECs expressing EphB receptors into the intersomitic region where ephrin-B2 expression is normally absent. CAGp-ephrin-B2 Tg mice show sudden death at neonatal stages from aortic dissecting aneurysms due to defective recruitment of vascular smooth muscle cells to the ascending aorta. EphB/ephrin-B2 signaling between endothelial cells and surrounding mesenchymal cells plays an essential role in vasculogenesis, angiogenesis, and vessel maturation.
Oike
Yuichi
Y
Department of Cell Differentiation, the Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
Ito
Yasuhiro
Y
Hamada
Koichi
K
Zhang
Xiu-Qin
XQ
Miyata
Keishi
K
Arai
Fumio
F
Inada
Tomohisa
T
Araki
Kimi
K
Nakagata
Naomi
N
Takeya
Motohiro
M
Kisanuki
Yaz Y
YY
Yanagisawa
Masashi
M
Gale
Nicholas W
NW
Suda
Toshio
T
D000199:Actins / Q000235:genetics; D000784:Aortic Dissection / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D001014:Aortic Aneurysm / Q000235:genetics; D001808:Blood Vessels / Q000196:embryology*; D002196:Capillaries / Q000378:metabolism; D002460:Cell Line; D003587:Cytomegalovirus / Q000235:genetics; D004730:Endothelium, Vascular / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D036388:Ephrin-B2; D015870:Gene Expression; D005914:Globins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D008648:Mesoderm / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012326:RNA Splicing; D020794:Receptor Protein-Tyrosine Kinases / Q000502:physiology; D036081:Receptors, Eph Family; D015398:Signal Transduction
D000199:Actins; D036388:Ephrin-B2; D008565:Membrane Proteins; D005914:Globins; D020794:Receptor Protein-Tyrosine Kinases; D036081:Receptors, Eph Family