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(Circulation Research. 2008;102:637.)
© 2008 American Heart Association, Inc.

Review

Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis

Matthew T. Holderfield, Christopher C.W. Hughes

From the Department of Molecular Biology & Biochemistry, University of California, Irvine.

Correspondence to C.C.W. Hughes, PhD, 3219 McGaugh Hall, Department of Molecular Biology & Biochemistry, University of California, Irvine, CA 92697. E-mail cchughes{at}uci.edu

This Review is part of a thematic series on Notch in the Cardiovascular System, which includes the following articles:

Crosstalk Between Vascular Endothelial Growth Factor, Notch, and Transforming Growth Factor-β in Vascular Morphogenesis

Notch and Vascular Smooth Muscle Phenotype

Notch Signaling in Cardiac Development
Aly Karsan Guest Editor

Vascular morphogenesis encompasses a temporally regulated set of morphological changes that endothelial cells undergo to generate a network of interconnected tubules. Such a complex process inevitably involves multiple cell signaling pathways that must be tightly coordinated in time and space. The formation of a new capillary involves endothelial cell activation, migration, alignment, proliferation, tube formation, branching, anastomosis, and maturation of intercellular junctions and the surrounding basement membrane. Each of these stages is either known or suspected to fall under the influence of the vascular endothelial growth factor, notch, and transforming growth factor-β/bone morphogenetic protein signaling pathways. Vascular endothelial growth factor is essential for initiation of angiogenic sprouting, and also regulates migration of capillary tip cells, proliferation of trunk cells, and gene expression in both. Notch has been implicated in the regulation of cell fate decisions in the vasculature, especially the choice between arterial and venular endothelial cells, and between tip and trunk cell phenotype. Transforming growth factor-β regulates cell migration and proliferation, as well as matrix synthesis. In this review, we emphasize how crosstalk between these pathways is essential for proper patterning of the vasculature and offer a transcriptional oscillator model to explain how these pathways might interact to generate new tip cells during retinal angiogenesis.

Key Words: angiogenesis • endothelial cell differentiation • transcriptional regulation • vascular endothelial growth factor • vascular endothelial growth factor receptors