Inhibition of Notch signalling induces extensive intussusceptive neo‐angiogenesis by recruitment of mononuclear cells

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Objectiveto evaluate the effects of Notch inhibition on the vasculature using chick area vasculosa and MxCre Notch1(lox/lox) mice and to test to which extent this effect is mediated by ephrinB2/EphB4.Methods and ResultsInhibition of Notch signaling by Y secretase 1 induced significantly intussusceptive angiogenesis (IA) forming large immature capillary plexus. The latter it is characterized by 40% increased vascular density, pericyte detachment, increased transpermeability and recruitment of mononuclear cells to the sites of new formed transluminal tissue pillars (sign of IA). The process was dramatically enhanced when Notch inhibition was combined with the injection of chicken or mouse bone marrow‐derived mononuclear cells. Along with the morphological alterations of IA, we observed down‐regulation of ephrinB2 mRNA levels. Inhibition of ephrinB2 and EphB4 signaling induces pericytes detachment and significantly upregulation of VEGFR1 but without angiogenic response and recruitment of mononuclear cells. Remarkable, the chemotactic factors SDF‐1 and CXCR4 were up‐regulated only due to the Notch inhibition.ConclusionsOur results indicated that Notch inhibition disturbs vessel stability, induces extravasation of mononuclear cells of bone marrow origin by up‐regulation SDF‐1/CXCR4 chemotactic factors. Recruited cells contributed to formation of transluminal tissue pillars i.e. intussusceptive neo‐angiogenesis, triggering in this way the augmentation of the capillary plexus but without the accompanying vascular maturation and remodeling. .