Induction of Endothelial Cell Chemotaxis by Sphingosine 1-Phosphate and Stabilization of Endothelial Monolayer Barrier Function by Lysophosphatidic Acid, Potential Mediators of Hematopoietic Angiogenesis

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Abstract
Angiogenesis, the formation of new blood vessels, is an important component of restoration of hematopoiesis after BMT, but the mediators involved in hematopoietic angiogenesis have not been identified. We examined the influence of the lipid growth factors, phosphatidic acid (PA), lysophosphatidic acid (LPA), and sphingosine 1-phosphate (S1P), on several angiogenic properties of endothelial cells, including migration and stabilization of vascular barrier integrity. In a previous study, PA was found to disrupt the permeability of established endothelial monolayers, an early event in the angiogenic response that liberates cells for subsequent mobilization. In the present study, both PA and LPA weakly induced the chemotactic migration of endothelial cells from an established monolayer. The chemotactic response induced by PA and LPA was similar in intensity to that observed with optimal levels of the known protein endothelial cell chemoattractants, basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). A markedly greater chemotactic response was effected by nanomolar concentrations of S1P, indicating that this platelet-derived factor plays an important role in a key aspect of angiogenesis, chemotactic migration of endothelial cells. The chemotactic response to S1P was completely inhibited by preincubation of endothelial cells with antisense oligonucleotides to the high-affinity S1P receptor, Edg-1. In addition, chemotaxis of endothelial cells to S1P was inhibited by preincubation of cells with specific inhibitors of tryosine kinases, but inhibitors of phosphatidylinositol 3 ' kinase had little effect. Finally, LPA effectively stabilized endothelial monolayer barrier function, a late event in angiogenesis. Thus, the phospholipid growth factors, PA, S1P, and LPA, display divergent and potent effects on angiogenic properties of endothelial cells and giogenic differentiation of endothelial cells potentially act in tandem to effectively induce neovascularization. These mediators may thus exert important roles in restoration of hematopoiesis, as they facilitate blood vessel formation at sites of transplanted stem cells, allowing the progeny of engrafted progenitors to move from marrow sinusoids to the peripheral vasculature.