Magnetic Resonance Imaging Investigation of Axonal Remodeling and Angiogenesis after Embolic Stroke in Sildenafil-Treated Rats

Abstract

Interaction between angiogenesis and axonal remodeling after stroke was dynamically investigated by MRI in rats with or without sildenafil treatments. Male Wistar rats were subjected to embolic stroke and treated daily with saline (n=10) or with sildenafil (n=11) initiated at 24 h and subsequently for 7 days after onset of ischemia. T(2)(*)-weighted imaging, cerebral blood flow (CBF), and diffusion tensor imaging (DTI) measurements were performed from 24 h to 6 weeks after embolization. T(2)(*) and fractional anisotropy (FA) maps detected angiogenesis and axonal remodeling after stroke, respectively, starting from 1 week in sildenafil-treated rats. Areas demarcated by MRI with enhanced angiogenesis, elevated local CBF, and augmented axonal remodeling were spatially and temporally matched, and FA values were significantly correlated with the corresponding CBF values (R=0.66, P<4 x 10(-5)) at 6 weeks after stroke. Axonal projections were reorganized along the ischemic boundary after stroke. These MRI measurements, confirmed by histology, showed that sildenafil treatment simultaneously enhanced angiogenesis and axonal remodeling, which were MRI detectable starting from 1 week after stroke in rats. The spatial and temporal consistency of MRI metrics and the correlation between FA and local CBF suggest that angiogenesis, by elevating local CBF, promotes axonal remodeling after stroke.

Phosphodiesterase‐5 inhibition potentiates cerebrovascular reactivity in chronic traumatic brain injury

“…PDE5 inhibitors, like sildenafil, extend the action of normally short‐lived cGMP and improve microvascular function when endothelial cells fail to produce sufficient NO. Furthermore, in studies on stroke animal models, sildenafil appears to have angiogenic properties in addition to its immediate vasodilatory effects 41, 42, 43, 44, 45. Sildenafil enters the brain readily and is a good candidate therapy for TCVI because of these vasodilatory and microvascular reparative properties.…”

In Vivo Inhibition of miR-155 Promotes Recovery after Experimental Mouse Stroke

“…In offline analyses using ImageJ, the fluorescence of five randomly chosen regions of interest over the vessel areas and five to 10 areas over perivascular brain parenchyma in both lesioned and nonlesioned/intact hemispheres were measured. The obtained measurements in the interstitial space were normalized to the maximal fluorescence intensity in the blood vessels and expressed as a percentage fluorescence intensity (modified from Egawa et al, 2013). Thirty minutes after fluorescein-dextran injection in a healthy brain, bright vessels filled with fluorescein-dextran are seen clearly over the dark background of unstained tissue, reflecting intact BBB.…”

“…A subacute phase of ischemia is associated with postischemic vascular remodeling (Ding et al, 2008;Beck et al, 2009) and our aim is to find a way to promote this natural regeneration process. The present investigation introduces a novel approach to cerebral regeneration: regulation of the vascular functions and overall recovery through direct modulation of specific miRNA activity.…”

Sildenafil Improves Epicenter Vascular Perfusion but not Hindlimb Functional Recovery after Contusive Spinal Cord Injury in Mice

“…Indeed, while acute neurological improvements following sildenafil administration have been reported in a spinal ischemia model (Kiymaz et al, 2008), no significant acute functional improvements following tadalafil administration could be found acutely after trauma in a weight drop model of SCI (Serarslan et al, 2010). Additionally, our rationale for a more chronic duration of treatment was to assess the potential benefits of improving angiogenesis after injury, as observed after embolic stroke (Ding et al, 2008;Li et al, 2007;Zhang et al, 2006), in addition to the potential vasodilatory protective effects of a more acute administration. While we observed no increase in angiogenesis following sildenafil treatment 7 days post-injury, we cannot exclude the possibility that sildenafil had an earlier but unsustainable effect on epicenter or penumbral microvasculature following injury.…”

“…Indeed, enhancing NO/cGMP signaling via administration of the cGMP phosphodiesterase inhibitors sildenafil or tadalafil has been shown to increase CNS angiogenesis in a rat ischemic model of embolic stroke (Ding et al, 2008;Li et al, 2007;Zhang et al, 2006).…”