Bone marrow mononuclear cell transplantation promotes therapeutic angiogenesis via upregulation of the VEGF–VEGFR2 signaling pathway in a rat model of vascular dementia

Abstract

Bone marrow mononuclear cells (BMMNCs) are important for angiogenesis after stroke. We investigated the effects of BMMNCs on cognitive function, angiogenesis, and the vascular endothelial growth factor (VEGF)-VEGF receptor 2 (VEGFR2) signaling pathway in a rat model of vascular dementia. We transplanted BMMNCs into rats that had undergone permanent bilateral occlusion of the common carotid arteries (2VO) and observed their migration in vivo. On day 28, we assessed cognitive function with the Morris Water Maze test and examined vascular density and white matter damage within the corpus striatum by staining with fluorescein lycopersicon esculentum (tomato) lectin or Luxol fast blue. We evaluated expression of VEGF, rapidly accelerated fibrosarcoma 1 (Raf1), and extracellular-signal-regulated kinases 1 and 2 (ERK1/2) in the ischemic hemisphere by Western blot analysis on day 7 after cell transplantation. Contribution of the VEGF-VEGFR2 signaling pathway was confirmed by using VEGFR2 inhibitor SU5416. BMMNCs penetrated the blood-brain barrier and reached the ischemic cortex and white matter or incorporated into vascular walls of 2VO rats. BMMNC-treated 2VO rats had better learning and memory, higher vascular density, and less white matter damage than did vehicle-treated rats. The beneficial effects of BMMNCs were abolished by pretreatment of rats with SU5416. Protein expression of VEGF and phosphorylated Raf1 and ERK1/2 was also significantly increased by BMMNC treatment, but this upregulation was reversed by SU5416. BMMNCs can enhance angiogenesis, reduce white matter damage, and promote cognitive recovery in 2VO rats. The angiogenic effect may result from upregulation of the VEGF-VEGFR2 signaling pathway.

Autologous Bone Marrow Mononuclear Cells Exert Broad Effects on Short- and Long-Term Biological and Functional Outcomes in Rodents with Intracerebral Hemorrhage

“…We also examined the effect of MNCs on vessel density. Several studies have shown that MNCs provide protection in a model of chronic cerebral ischemia-induced cognitive dysfunction by increasing angiogenesis [50,51]. Others have demonstrated that MNCs increase vascular density and blood flow in various ischemic disorders such as cardiovascular disease, peripheral arterial disease, and diabetic foot [52].…”

A modified bilateral carotid artery stenosis procedure to develop a chronic cerebral hypoperfusion rat model with an increased survival rate

“…Sections were stained with Luxol fast blue (LFB) to evaluate the amount of myelin in the WM as previously described (Wang et al, 2014;Wu et al, 2012). Three sections per rat were obtained, and three randomly chosen fields from the middle of the corpus callosum and the corpus striatum of each section were captured under light microscopy at the same exposure level.…”

“…However, the abrupt decrease in CBF during the acute phase after the 2VO procedure causes substantial mortality rates in rats (50-60%) (Wang et al, 2014;Shibata et al, 2004). Many modified 2VO protocols have been explored to minimize the number of animals used in research by alleviating the sudden reduction of CBF.…”

Altered Long Noncoding RNA and Messenger RNA Expression in Experimental Intracerebral Hemorrhage - a Preliminary Study

“…Vascular endothelial growth factor receptor-2 (VEGFR-2) is a type III transmembrane receptor. VEGF binding to VEGFR-2 leads to the receptor autophosphorylation (activation), which initiates several downstream signalings [56, 57]. However, as the protein level of VEGF decreases 7 to 14 days following ICH, the p-VEGFR-2 signaling becomes weaker and weaker [58].…”