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H. Katsuta, A. Uemura, J. Kiryu, Y. Honda, S.–I. Nishikawa; Controlof vessel patterning by heterotypic endothelial interactions . Invest. Ophthalmol. Vis. Sci. 2004;45(13):5342.
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Purpose: For the construction of hierarchical architecture, growing blood vessels are remodeled from primary capillary plexus, accompanying sprouting, branching, and regression of endothelial tubes. During these series of morphogenetic processes, endothelial cells (ECs) are specified to some heterogeneous populations, especially in arterial and venous vessels, which have been proven to be crucial for vascular remodeling. To date, however, little is understood about the significance of this endothelial heterogeneity and interactions among heterotypic ECs for the proper organization of vascular network. Here, taking advantages of postnatal angiogenesis of murine retina, in which these consecutive processes during vascular development can be observed sequentially, we performed morphological and molecular investigations in order to elucidate the mechanism of organized vascular patterning. Methods: Immunohistochemical analysis of murine developing retinal vasculature was performed to investigate the influences of various interventions as well as the normal development. Results: The time course expression of ephrinB2 and EphB4 in arterial and venous ECs, respectively, was identified. The expression pattern of endothelial ephrinB2 strongly suggested that it is induced by some extrinsic cues, such as circulating blood flow, in the course of vascular remodeling. However, once the ephrinB2/EphB4 identity was established, it was maintained for at least 48 hours even after the disappearance of blood flow. In addition, establishment of this EC identity was independent from association with perivascular mural cells, which display morphologically and molecularly distinct characters depending on the vessel sites. To assess how vascular remodeling is regulated by specification and interactions among heterotypic ECs, we manipulated ephrin and Notch signaling system which are assumed to play crucial roles at sites of heterotypic cell contacts. Uniform stimulation of receptors for ephrinB2 dramatically decreased capillary branching and density, which might be caused by excessive repulsion in endothelial cells expressing Eph receptors. Similarly, stimulation or neutralization of Notch receptors that are expressed in retinal vessels resulted in defective capillary formation. Conclusions: Development of heterogeneous EC identities and proper cellular interactions among them must be essential for normal patterning of growing blood vessels.
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