We speculate that under DF, elevated RSPO-3 and WNT5A act synergistically to increase signalling through FZD4 and Ryk, leading to increased transcriptional activity of β-catenin and expression of genes that promote the formation of stress fibres, disorganisation of adherens junctions, increased permeability and endothelial dysfunction. The gene discussed is FZD4; the disease is endothelial dysfunction.