Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization.

Background: Despite accumulating evidence that proves the pivotal role of endothelial progenitor cells (EPCs) in ischemic neovascularization, the key signaling cascade that regulates functional EPC kinetics remains unclear.

Methods And Results: In this report, we show that inactivation of specific Jagged-1 (Jag-1)-mediated Notch signals leads to inhibition of postnatal vasculogenesis in hindlimb ischemia via impairment of proliferation, survival, differentiation, and mobilization of bone marrow-derived EPCs. Bone marrow-derived EPCs obtained from Jag-1-/- mice, but not Delta-like (Dll)-1-/- mice, demonstrated less therapeutic potential for ischemic neovascularization than EPCs from the wild type. In contrast, a gain-of-function study using 3T3 stromal cells overexpressing Notch ligand revealed that Jag-1-mediated Notch signals promoted EPC commitment, which resulted in enhanced neovascularization. The impaired neovascularization in Jag-1-/- mice was profoundly rescued by transplantation of Jag-1-stimulated EPCs.

Conclusions: These data indicate that specific Jag-1-derived Notch signals from the bone marrow microenvironment are critical for EPC-mediated vasculogenesis, thus providing an important clue for modulation of strategies for therapeutic neovascularization.