Receptor tyrosine kinase signaling in vascular development

The formation and maintenance of the vascular circulatory system is of utmost importance during embryonic and postnatal life. The first organ system to develop is the cardiovascular network of endothelial cells that carry blood cells and metabolites throughout the embryo (1, 2). Indeed, a functional vascular system is crucial for the rapid growth of postimplantation embryos. The vascular system is highly dynamic throughout life and is able to generate new capillary endothelial cell networks as required, such as in wound healing and in the cyclic neovascularization of the ovarian follicle (corpus luteum) and endometrium. Diseases of the cardiovascular system, including those of the heart and blood vessels, are a major cause of pathological conditions affecting humans. Moreover, many cancer cells secrete angiogenic factors that attract endothelial cells to neovascularize and divert blood flow into solid tumors (3, 4). Abnormal angiogenesis is also observed in nonneoplastic conditions, including diabetic retinopathy, rheumatoid arthritis, and psoriasis (4). Our ability to understand the biochemical mechanisms that govern and control vascular endothelial cells are thus essential to the development of new therapies to help combat such disorders. Endothelial cells must respond to a diverse array of potential signals and initiate downstream intracellular pathways that can affect their fate, proliferation, transcription, migration, adherence, and permeability. Some of these signals may be elicited by transmembrane RTKs, because a select group of these molecules are expressed at high levels primarily in cells of the endothelial lineage, including Flk-1/KDR, Flt-1, Flt-4, Tie-1, and Tie-2/Tek (5). Furthermore, a family of growth factors that act specifically on endothelial cells, VEGFs, have been identified as ligands capable of stimulating the tyrosine kinase activity of the Flk-1, Flt-1, and Flt-4 receptors. In this review, we describe recent genetic studies in mice that directly implicate signaling pathways activated by these endothelial- specific RTKs as key regulators of vascular development.