Abstract
Previous studies have shown that the pial microcirculation remodeling improves neurological outcome after middle cerebral artery occlusion (MCAO), accompanied by higher expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), modulating in vivo angiogenesis. This study was aimed to assess the effects of bone marrow mesenchymal stem cells (BM-MSCs) infused after MCAO on rat pial microcirculation. Animals were subjected to 2 h MCAO followed by BM-MSCs infusion into internal carotid artery. Pial microcirculation was observed at different reperfusion times by fluorescence microscopy. Geometric characteristics of arteriolar networks, permeability increase, leukocyte adhesion, perfused capillary density, VEGF, and endothelial nitric oxide synthase (e-NOS) expression were evaluated. Green fluorescent protein (GFP)-BM-MSCs were used to evaluate their distribution and cell phenotype development during reperfusion. BM-MSCs stimulated a geometric rearrangement of pial networks with formation of new anastomotic vessels sprouting from preexistent arterioles in the penumbra at 7–14–28 days of reperfusion. At the same time VEGF and eNOS expression increased. GFP-BM-MSCs appear to be involved in endothelial and smooth muscle cell programming in the infarcted area. In conclusion, transient MCAO induced pial vascular remodeling characterized by arteriolar anastomotic arcades (originated from preexistent arterioles in penumbra area) able to overlap the ischemic core supplying blood to the neuronal tissue. BM-MSCs appear to accelerate angiogenic processes facilitating new vessel formation; this mechanism was promoted by an increase in VEGF and eNOS expression.
Highlights
Pial microcirculation remodeling improves neurological outcome after middle cerebral artery occlusion (MCAO), accompanied by higher expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase, modulating in vivo angiogenesis, as previously observed (Li et al, 2002; Lapi et al, 2008, 2013; Komatsu et al, 2010)
We observed that the pial microcirculation was progressively reorganized attaining full recovery at 28 days of reperfusion: the capillary density significantly increased, while microvascular permeability and leukocyte adhesion markedly decreased, compared with animals observed at shorter times of reperfusion (Lapi et al, 2013)
VEGF, endothelial nitric oxide synthase (eNOS), nNOS, and iNOS Expression at 7, 14, and 28 Days of Reperfusion We evaluated the expression of VEGF and the three different NOS proteins in the ipsilesional (IPSI) temporoparietal cortex and striatum of rats subjected to MCAO plus Bone marrow mesenchymal stem cells (BM-MSCs) at different reperfusion time intervals: 7, 14, and 28 days compared with the expression of the same proteins in untreated rats
Summary
Pial microcirculation remodeling improves neurological outcome after middle cerebral artery occlusion (MCAO), accompanied by higher expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS), modulating in vivo angiogenesis, as previously observed (Li et al, 2002; Lapi et al, 2008, 2013; Komatsu et al, 2010). BM-MSCs migrate selectively into damaged brain areas after intravenous injection at an early phase after ischemia (Honma et al, 2006; Chavakis et al, 2008). Specific molecular signals, such as stromal cell-derived factor-1 (SDF-1/CXCR4) intracellular signaling, adhesion molecules and proteases are involved in the interaction of BM-MSCs to reach, recognize, and function in cerebral ischemic tissue (Chavakis et al, 2008). When cultured in presence of endothelial growth supplements, the cells start to express endothelial markers (Oswald et al, 2004)
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