Estrogen Defines the Dorsal-Ventral Limit of VEGF Regulation to Specify the Location of the Hemogenic Endothelial Niche

The genetic control of hematopoietic stem and progenitor cell (HSPC) function is increasingly understood, however less is known about the interactions specifying the embryonic hematopoietic niche. Here, we report 17β-estradiol (E2) influences the production of runx1+ HSPCs in the AGM region by antagonizing VEGF-signaling and subsequent assignment of hemogenic endothelial (HE) identity. Exposure to exogenous E2 during vascular niche development (12–24hpf) significantly disrupted flk1+ vessel maturation, ephrinB2+ arterial identity and specification of scl+ HE by decreasing the expression of VEGFAa and downstream arterial Notch-pathway components; heat-shock induction of VEGFAa/Notch rescued E2-mediated hemato-vascular defects. Conversely, repression of endogenous E2-activity increased somitic VEGF expression and vascular-target regulation, shifting the assignment of arterial/venous fate and HE localization; blocking E2-signaling allowed venous production of scl+/runx1+ cells, independent of arterial identity acquisition. Together, these data suggest yolk-derived estrogen sets the ventral boundary of hemogenic vascular niche specification by antagonizing the dorsal-ventral limits of VEGF regulation.