Vascular and Biology 01

Abstract

Background: Endothelin-1 (ET-1) is a 21 amino acid peptide with vasoconstrictor and mitogenic properties. We observed that ET-1 is expressed around areas of angiogenesis in ischaemic skeletal muscle, and sought to determine whether ET-1 provides an angiogenic stimulus to human microvascular cells. Methods: Human dermal microvascular cells (HMEC-1) were grown on growth factor reduced Matrigel, with or without ET-1 at various concentrations. Synergy with the angiogenic factor vascular endothelial growth factor (VEGF) was sought by co-adding ET-1 with VEGF. In addition, we measured the effects of selective inhibitors of the ET-1 receptor. Angiogenesis was measured after 24-h treatment by visual analysis of microvessel growth and by scanning the mean optical density of images of the angiogenic field. Results: ET-1 enhanced angiogenesis in the presence of VEGF (P < 0.02). The ET(B) receptor antagonist BQ788 suppressed angiogenesis below basal levels (P < 0.04), whereas the ET(A) receptor antagonist had no effect. Microvascular cells were found to release ET-1 when grown on Matrigel, with enhancement following treatment with VEGF. Conclusions: These data suggest that in human microvascular cells, ET-1 is an important autocrine growth factor, acting downstream and in concert with VEGF to stimulate angiogenesis. We suggest that the mitogenic properties of ET-1 are ET(B) mediated, unlike the effects on vascular tone, which are ET(A) mediated. The separation of these effects might provide benefit to patients with peripheral vascular disease, where selective ET(A) receptor antagonists could promote vasodilatation whilst preserving the ET(B) mediated angiogenic effects.