Traumatic spinal cord injury (SCI) is complicated by secondary pathology that increases tissue loss and exacerbates functional recovery beyond the initial physical impact. Destruction of the vasculature that supports spinal cord tissue compromises blood spinal cord barrier integrity and is a major impediment to tissue sparing and regeneration. While formation of new blood vessels occurs robustly 3-7 days after contusive injury, the vessels are leaky, contributing to inflammation and edema. Thus, it is unclear at this time whether neovascularization facilitates or impairs tissue loss and functional recovery. Notch signaling, which is critical to vascular development and pathological angiogenesis, is known to regulate vascular sprouting through formation of tip cells and to control endothelial cell proliferation. Importantly, increased Notch signaling facilitates the maturation of vessels. Although fewer in number, these vessels are larger, less leaky, and are capable of supporting growing tissue (Noseda et al., 2004;Harrington et al., 2007;Li et al., 2007). We hypothesize that by promoting the maturation of vessels formed 3-7 days post-SCI, inflammation and tissue loss will be attenuated and functional recovery improved. Controlled proliferation with enhanced vessel maturation would provide evidence to control or attenuate angiogenic treatment in the first week following SCI. Conversely, increased endothelial cell proliferation leading to a greater vascular density by 7 days post-SCI may relieve the ischemia and hypoxia that contributes to tissue loss. Moreover, attenuation of the inflammatory response by decreasing pro-inflammatory activation of the microvascuiature may significantly impede repair processes. This observation would support the use of pro-angiogenic treatments that increase numbers of vessels in the absence of controlled permeability and enhanced blood spinal cord barrier integrity. Importantly, it is critical to determine the impact the manipulation of Notch signaling has not only on the vasculature but also inflammation and tissue loss due to secondary pathology.
Taken together, it is expected that the proposed experiments will provide evidence not only to support the role of Notch in new blood vessel formation after SCI but facilitate studies that seek to target acute vascular responses to enhance functional, locomotor recovery.
|Fassbender, Janelle M; Saraswat-Ohri, Sujata; Myers, Scott A et al. (2012) Deletion of endoplasmic reticulum stress-induced CHOP protects microvasculature post-spinal cord injury. Curr Neurovasc Res 9:274-81|
|Fassbender, Janelle M; Myers, Scott A; Whittemore, Scott R (2011) Activating Notch signaling post-SCI modulates angiogenesis in penumbral vascular beds but does not improve hindlimb locomotor recovery. Exp Neurol 227:302-13|
|Fassbender, Janelle M; Whittemore, Scott R; Hagg, Theo (2011) Targeting microvasculature for neuroprotection after SCI. Neurotherapeutics 8:240-51|