There is a potential for self-repair after adult or neonatal stroke, but endogenous neurogenesis is short- lived and ineffective. Our goal is to enhance the repair after neonatal stroke. Angiogenesis facilitates neurogenesis after adult stroke through the formation of a "neurovascular niche." Brain macrophages can modulate repair and functional recovery after stroke through effects on the brain microenvironment and direct effects on angiogenesis and neurogenesis. Galectin-3 (Gal-3) has recently been implicated in the process of angiogenesis. The postulated ability of Gal-3 to provide a "docking point" for the formation of a neurovascular niche and to mediate VEGF-induced angiogenesis makes this molecule an attractive target for enhancing repair, but its effect on repair after neonatal stroke is not known. We hypothesize that microglia/macrophages critically affect long-term recovery after neonatal stroke, in part through enhanced Gal-3-dependent angiogenesis. Using our established models of transient middle cerebral artery occlusion in neonatal rats and mice, we wil determine whether angiogenesis and neurogenesis depend on Gal-3 produced in brain macrophages.
In Aim 1, we will determine the effects of microglial depletion on angiogenesis and neurovascular niche formation after neonatal stroke. We will monitor axonal outgrowth in living animals by bioluminescence.
In Aim 2, we will investigate the effects of enhanced or disrupted Gal-3 signaling on endothelial activation in living rats by ultrasound enhanced with specific molecular probes to target ?vss3 integrin. Repair will be further studied in neonatal ischemic Gal-3 knockout mice bearing the dual luc/gfp reporter under the TLR2 promoter.
In Aim 3, we will delineate neurovascular niche formation folowing Gal-3 or VEGFR2 inhibition in injured living rats by using ultrasound and specific probes for VEGFR2. VEGF-mediated angiogenesis will be determined in injured Gal-3 knockout mice. Functional consequences of microglial depletion and Gal-3 manipulations after neonatal stroke will be determined. Understanding the mechanisms regulating repair is an important first step on the way to successful bench-to-bed translation to enhance repair in injured newborn brains.
Stroke in the term newborn occurs in 1 in 4000 live births. Most infants survive with significant long-term disabilities. Understanding how to enhance recovery from stroke is critical for alleviating the suffering of children and decreasing the enormous cost to families and society.
|Dzietko, M; Derugin, N; Wendland, M F et al. (2013) Delayed VEGF treatment enhances angiogenesis and recovery after neonatal focal rodent stroke. Transl Stroke Res 4:189-200|