Abstract
The secretion of angiogenic factors by vascular endothelial cells is one of the key mechanisms of angiogenesis. Here we report on the isolation of a new potent angiogenic factor, diuridine tetraphosphate (Up4U) from the secretome of human endothelial cells. The angiogenic effect of the endothelial secretome was partially reduced after incubation with alkaline phosphatase and abolished in the presence of suramin. In one fraction, purified to homogeneity by reversed phase and affinity chromatography, Up4U was identified by MALDI-LIFT-fragment-mass-spectrometry, enzymatic cleavage analysis and retention-time comparison. Beside a strong angiogenic effect on the yolk sac membrane and the developing rat embryo itself, Up4U increased the proliferation rate of endothelial cells and, in the presence of PDGF, of vascular smooth muscle cells. Up4U stimulated the migration rate of endothelial cells via P2Y2-receptors, increased the ability of endothelial cells to form capillary-like tubes and acts as a potent inducer of sprouting angiogenesis originating from gel-embedded EC spheroids. Endothelial cells released Up4U after stimulation with shear stress. Mean total plasma Up4U concentrations of healthy subjects (N = 6) were sufficient to induce angiogenic and proliferative effects (1.34±0.26 nmol L-1). In conclusion, Up4U is a novel strong human endothelium-derived angiogenic factor.
Highlights
Vasculature in adult mammals is mainly quiescent; new blood vessel formation is required for timely tissue repair and remodeling after injury [1]
Interest has focused on peptidic angiogenic factors such as the vascular endothelial growth factors, hepatocyte growth factor or fibroblast growth factor, and non-peptidic, low molecular angiogenic factors such as adenosine or hypoxic metabolites, e. g. lactate or pyruvate, which mediate hypoxia-induced angiogenesis
Experiments comparing the phenotypic characteristics of HMEC-1 cells with human dermal microvascular endothelial cells or human umbilical vein endothelial cells revealed that HMEC-1 cells show features of both, small- and large-vessel endothelial cells [13]
Summary
Vasculature in adult mammals is mainly quiescent; new blood vessel formation is required for timely tissue repair and remodeling after injury [1]. The process of angiogenesis involves migration, proliferation, differentiation, and adhesion of multiple cell types, including endothelial, mural, and inflammatory cells [3,4]. Disease processes such as cancer growth [5], diabetic retinopathy or chronic inflammation are dependent on angiogenesis [6]. Our knowledge about the mediators secreted by endothelial cells inducing angiogenesis is just at the beginning Unravelling these mediators involved in angiogenesis would offer therapeutic options to ameliorate disorders that are currently leading causes of mortality and morbidity, including cardiovascular diseases, cancer, chronic inflammatory disorders, diabetic retinopathy, excessive tissue defects, and chronic non-healing wounds. The knowledge of the endogenous mediators involved provides numerous opportunities for therapeutic intervention [8]
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