Abstract
Thrombolysis remains the only beneficial therapy for ischemic stroke, but is restricted to a short therapeutic window following the infarct. Currently research is focusing on spontaneous regenerative processes during the sub-acute and chronic phase. Angiogenesis, the formation of new blood vessels from pre-existing ones, was observed in stroke patients, correlates with longer survival and positively affects the formation of new neurons. Angiogenesis takes place in the border zones of the infarct, but further insight into the temporal profile is needed to fully apprehend its therapeutic potential and its relevance for neurogenesis and functional recovery. Angiogenesis is a multistep process, involving extracellular matrix degradation, endothelial cell proliferation, and, finally, new vessel formation. Interaction between vascular endothelial growth factor and its receptor 2 (VEGFR2) plays a central role in these angiogenic signaling cascades. In the present study we investigated non-invasively the dynamics of VEGFR2 expression following cerebral ischemia in a mouse model of middle cerebral artery occlusion (MCAO). We used a transgenic mouse expressing firefly luciferase under the control of the VEGFR2 promotor to non-invasively elucidate the temporal profile of VEGFR2 expression after stroke as a biomarker for VEGF/VEGFR2 signaling. We measured each animal repetitively up to 2 weeks after stroke and found increased VEGFR2 expression starting 3 days after the insult with peak values at 7 days. These were paralleled by increased VEGFR2 protein levels and increased vascular volume in peri-infarct areas at 14 days after the infarct, indicating that signaling via VEGFR2 leads to successful vascular remodeling. This study describes VEGFR2-related signaling is active at least up to 2 weeks after the infarct and results in increased vascular volume. Further, this study presents a novel strategy for the non-invasive evaluation of angiogenesis-based therapies.
Highlights
Angiogenesis, the formation of new blood vessels from preexisting ones, is recognized as a potential new therapeutic target in ischemic stroke (Slevin et al, 2006; Navaratna et al, 2009; Shibuya, 2009)
We measured each animal repetitively up to 2 weeks after stroke and found increased VEGFR2 expression starting 3 days after the insult with peak values at 7 days. These were paralleled by increased VEGFR2 protein levels and increased vascular volume in peri-infarct areas at 14 days after the infarct, indicating that signaling via VEGFR2 leads to successful vascular remodeling
We continued to evaluate the photon emission (PE) of the 15th minute after luciferin injection (PE15), which represents maximum PE
Summary
Angiogenesis, the formation of new blood vessels from preexisting ones, is recognized as a potential new therapeutic target in ischemic stroke (Slevin et al, 2006; Navaratna et al, 2009; Shibuya, 2009). Angiogenesis is closely linked to neurogenesis and has shown positive effects on neuronal cell formation, migration and maturation (Taguchi et al, 2004). These results support the hypothesis, that angiogenesis after stroke is therapeutically advantageous. The absence of adequate blood supply caused by the blockage of a cerebral artery leads to tissue hypoxia, which triggers the angiogenic response (Marti et al, 2000; Beck and Plate, 2009). Activation of the VEGFR2 results in endothelial cell proliferation, migration and differentiation (Ferrara et al, 2003; Hayashi et al, 2006).
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