Blood vessel formation is regulated by local paracrine signals, both positive and negative. Many positive signaling mechanisms have been identified, but little is known about negative regulation. We have recently obtained evidence for a novel paracrine signaling mechanism that negatively regulates early vessel patterning. In higher vertebrates, vessel formation is initiated throughout the embryonic disc, except for the region along the midline body axis. The mechanism that inhibits vessel development along the midline is not known. Because the identity of the embryonic midline is specified by the notochord, we suspected that the notochord provides an instructive cue for producing a negative zone of vessel formation along the midline. Our preliminary data show that ablation of the notochord results in vessel formation at the midline zone. Ectopic implantation of the notochord gives rise to an ectopic inhibition of vessel formation. Furthermore, two notochord-derived paracrine factors, Chordin and Noggin, can inhibit endothelial cell migration in culture. These two paracrine factors are potent antagonists for BMP signaling. We therefore hypothesize that: 1) The notochord is the main source of paracrine factors responsible for the novel inhibitory mechanism of vessel formation at midline; 2) Endothelial cells are a direct target of the notochord-derived inhibitory signal; and 3) BMP antagonism is a molecular mechanism for inhibition of vessel development at the midline. We will test these hypotheses by: 1) both ablating and ectopically implanting the notochord and other midline tissues and assaying resulting vessel formation in the embryo; 2) determining the inhibitory activity of the notochord on purified embryonic endothelial cells in their migration and capillary tube formation; and 3) activating and inhibiting Chordin and Noggin functions in the embryo and analyzing alteration in the resulting vessel pattern. The studies proposed here will identify novel cellular and molecular mechanisms that negatively regulate vessel formation and build a foundation for rational therapeutics of vascular disorder in adults.
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