Activating Notch signaling post-SCI modulates angiogenesis in penumbral vascular beds but does not improve hindlimb locomotor recovery

Manipulation of Notch signaling has led to significant tumor shrinkage as well as recovery from several traumatic and ischemic injury models indicating its potential clinical application. We have tested both an agonist and antagonist of Notch signaling to study the effects of Notch-mediated angiogenesis on spinal cord vascular pathology following traumatic injury. Initial neonatal retinal vascularization assays showed their respective bioactivities in vivo. Mice were treated with either the antagonist Jagged1-Fc chimera (Jag1-Fc) or agonist Notch1 antibody (N1 Ab) immediately following a mid-thoracic contusive injury through an initial jugular bolus and tail vein injections for 3 days post-injury. After 14 days, activating Notch signaling decreased the overall vascular density within the penumbral gray matter compared to controls while maintaining the density of perfused vessels. Inhibiting Notch signaling did not change the density or perfusion of microvessels within the lesion penumbra. Furthermore, neither activation nor inhibition of Notch signaling significantly altered inflammation, hypoxia, and lesion volume in the epicenter and penumbra. Importantly, neither treatment changed locomotor function. In postnatal retinal vascular assays, administration of Jag1-Fc and N1 Ab increased and decreased both tip cell numbers and branch points in each treatment, respectively. However, these agents did not modulate primary CNS EC proliferation in vitro in spite of sufficient Notch ligand expression. We conclude that Notch signaling, while an important part of developmental angiogenesis, may play a lesser role in mediating vascular recovery following traumatic injury to the CNS.

Research Highlights► Increasing Notch signaling acutely after SCI alters vascular responses. ► Altering Notch does not reduce inflammatory responses. ► Altering Notch does not enhance chronic locomotor recovery. ► Notch signaling is not a viable therapeutic target for the treatment of SCI.