P-selectin, an important mediator of angiogenesis in females: the role of estradiol

Angiogenesis, or new blood vessel formation, is key in vasculoproliferative disorders including rheumatoid arthritis. Here we report that the mediation of angiogenesis by P-selectin, an important member of the selectin adhesion molecule family, is unexpectedly sex dependent. In vivo angiogenesis measured in a Matrigel plug, in a sponge granuloma, and in a corneal micropocket was consistently impaired in P-selectin gene deficient mice compared with wild-type mice, but only if the P-selectin-deficient mice were female. Estrogen appeared to be one significant mediator of P-selectin sensitivity. In vitro the chemotactic activity of soluble P-selectin for human dermal microvascular endothelial cells was augmented by 17β-estradiol (E₂). Conversely, an antibody blockade of P-selectin reduced E₂-induced sprout formation in female mouse corneal endothelial cell morphogenesis assays, inhibited E₂-induced endothelial cell signaling via the Src and mitogen-activated protein kinase pathways, and decreased E₂-induced secretion of angiogenic basic fibroblast growth factor. In addition to its classical roles in leucocyte extravasation, P-selectin may also contribute to a variety of inflammatory diseases as a sex-restricted angiogenic intermediary.