Specification of bone marrow sinusoids requires TIE2-mediated positive feedback involving COUP-TFII and VEGFR3

The bone marrow (BM) vascular network drives bone development and hematopoiesis, but the mechanisms governing its specialized sinusoidal architecture remain poorly characterized. Here, we show that the angiopoietin receptor TIE2 is highly expressed by BM sinusoidal endothelial cells (BM-SECs). Its endothelial deletion triggers sinusoidal capillarization, characterized by reduced vessel diameter and aberrant mural cell coverage. Mechanistically, TIE2 insufficiency downregulates VEGFR3 in BM-SECs within 48 h of induced endothelial Tek deletion, while leaving hepatic sinusoidal VEGFR3 unaffected. RNA-sequencing reveals that TIE2 insufficiency suppresses sinusoidal development pathways while upregulating arterial and angiogenic genes. We validate this phenotype using inducible Tek deletion mainly in VEGFR3 + SECs and in Angpt1 -insufficient mice. Furthermore, endothelial deletion of the transcription factor COUP-TFII ( Nr2f2 ) recapitulates these defects, reducing both BM sinusoidal TIE2 and VEGFR3 expression. Finally, induced endothelial deletion of Flt4 produces a similar phenotype. Together, our findings imply that ANGPT1/TIE2 and COUP-TFII form a reciprocal regulatory loop essential for BM sinusoidal specification by sustaining VEGFR3 expression.