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Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia.

ABSTRACT: The myoblast-mediated delivery of angiogenic genes represents a cell-based approach for targeted induction of therapeutic collateralization. Here, we tested the superiority of myoblast-mediated co-delivery of vascular endothelial growth factor-A (VEGF) together with platelet-derived growth factor-BB (PDGF-BB) on transpial collateralization of an indirect encephalomyosynangiosis (EMS) in a model of chronic cerebral ischemia. Mouse myoblasts expressing a reporter gene alone (empty vector), VEGF, PDGF-BB or VEGF and PDGF-BB through a single bi-cistronic vector (VIP) were implanted into the temporalis muscle of an EMS following permanent ipsilateral internal carotid artery occlusion in adult, male C57BL/6N mice. Over 84 days, myoblast engraftment and gene product expression, hemodynamic impairment, transpial collateralization, angiogenesis, pericyte recruitment and post-ischemic neuroprotection were assessed. By day 42, animals that received PDGF-BB in combination with VEGF (VIP) showed superior hemodynamic recovery, EMS collateralization and ischemic protection with improved pericyte recruitment around the parenchymal vessels and EMS collaterals. Also, supplementation of PDGF-BB resulted in a striking astrocytic activation with intrinsic VEGF mobilization in the cortex below the EMS. Our findings suggest that EMS surgery together with myoblast-mediated co-delivery of VEGF/PDGF-BB may have the potential to serve as a novel treatment strategy for augmentation of collateral flow in the chronically hypoperfused brain.

SUBMITTER: Marushima A

PROVIDER: S-EPMC7370608 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia.

Marushima Aiki A Nieminen Melina M Kremenetskaia Irina I Gianni-Barrera Roberto R Woitzik Johannes J von Degenfeld Georges G Banfi Andrea A Vajkoczy Peter P Hecht Nils N

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20190109 2

The myoblast-mediated delivery of angiogenic genes represents a cell-based approach for targeted induction of therapeutic collateralization. Here, we tested the superiority of myoblast-mediated co-delivery of vascular endothelial growth factor-A (VEGF) together with platelet-derived growth factor-BB (PDGF-BB) on transpial collateralization of an indirect encephalomyosynangiosis (EMS) in a model of chronic cerebral ischemia. Mouse myoblasts expressing a reporter gene alone (empty vector), VEGF, P ...[more]

PMID: 30621518

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Project description:ObjectiveAcupuncture significantly improves cognitive dysfunction in rats with chronic cerebral ischemia. However, the underlying signaling pathways remain unclear. This study investigates the role of the CKLF1/HIF-1α/VEGF/Notch1 signaling pathway in the acupuncture-mediated improvement of cognitive function in rats with chronic cerebral ischemia.MethodsMale SD rats were randomly divided into the normal control group, sham-operated group, 2-VO model group, 2-VO + acupuncture group, and 2-VO + Ginaton group (Ginkgo biloba extract 14.4 mg/kg/day), with 10 rats in each group. The 2-VO + acupuncture group received acupuncture at the Shuigou, Baihui, bilateral Fengchi, and bilateral Zusanli points for 14 consecutive sessions over 2 weeks. The rats' memory function was assessed using the Morris water maze and novel object recognition tests. Cerebral blood volume changes were measured using laser speckle imaging. Ultrastructural changes in microvessels were observed via transmission electron microscopy. Neuronal and myelin alterations were evaluated using HE staining, Nissl staining, and LFB myelin staining. The expression levels of CKLF1, CCR5, HIF-1α, VEGF, and Notch1 proteins were measured using Western blot, and multiple immunofluorescence staining was performed to assess the colocalization of CKLF1 and neurons.ResultsCompared with the 2-VO model group, acupuncture treatment reduced the latency period and increased the number of platform crossings in the Morris water maze test, and the 2-VO model group had a higher recognition index in the novel object recognition test. We found that acupuncture improved the condition of endothelial cells, repaired the morphology of the vascular lumen, and alleviated astrocyte edema. We also showed that acupuncture could ameliorate pathological damage in rats with chronic cerebral ischemia. Moreover, acupuncture reduced the expression of CKLF1, CCR5, and HIF-1α proteins in the hippocampus, decreased the fluorescence intensity of CKLF1 expression, and increased the fluorescence intensity of neurons in the hippocampal CA1 region.ConclusionAcupuncture may exert neuroprotective effects and improve cognitive dysfunction caused by chronic cerebral ischemia by regulating the CKLF1/HIF-1α/VEGF/Notch1 pathway to inhibit inflammatory factors and increase cerebral blood flow.

Dataset Information

Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia.

Publications

Balanced single-vector co-delivery of VEGF/PDGF-BB improves functional collateralization in chronic cerebral ischemia.

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