Poststroke Angiogenesis, Con
2015; Lippincott Williams & Wilkins; Volume: 46; Issue: 5 Linguagem: Holandês
10.1161/strokeaha.114.007642
ISSN1524-4628
AutoresJoanna Adamczak, Mathias Hoehn,
Tópico(s)Cancer, Hypoxia, and Metabolism
ResumoHomeStrokeVol. 46, No. 5Poststroke Angiogenesis, Con Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBPoststroke Angiogenesis, ConDark Side of Angiogenesis Joanna Adamczak, PhD and Mathias Hoehn, PhD Joanna AdamczakJoanna Adamczak From the In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany. and Mathias HoehnMathias Hoehn From the In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Cologne, Germany. Originally published26 Mar 2015https://doi.org/10.1161/STROKEAHA.114.007642Stroke. 2015;46:e103–e104Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2015: Previous Version 1 Angiogenesis, the regrowth of new blood vessels, occurs after stroke1 and thus raises hopes that this regeneration is beneficial for patients with stroke. There is no doubt, that the restoration of blood supply, providing oxygen and nutrients to the ischemic brain tissue, is beneficial for stroke recovery. However, it is debated, whether angiogenesis truly contributes to improved recovery. Thus, fully functional new vessels occur only after several days,2 as angiogenesis is a multistep process. It is, therefore, important to have a close look at the angiogenic dynamics itself and to critically assess some pathophysiologic steps, which can be even aggravating stroke progression.Angiogenic cues arise from periods of hypoxia. Vascular endothelial growth factor (VEGF) is the most potent trigger for inducing angiogenesis and shows high upregulation as early as 1 hour after stroke. Unfortunately, it also regulates vascular permeability.3 Consequently, studies using VEGF delivery as a treatment for enhancing poststroke angiogenesis revealed not only positive effects but also negative effects. The therapeutic stimulation of angiogenesis with VEGF is clearly dependent on the route and timing of administration. In general, local and subacute administration is better tolerated than systemic and acute delivery.4 Intravenous administration of VEGF early after stroke to speed up blood supply improvement led to blood brain–barrier leakage and, in consequence, aggravated vasogenic edema and increased infarct volume. Investigations of VEGF-induced blood brain–barrier leakage revealed that blocking VEGF after hypoxia or ischemia reduces vascular leakage, brain edema, and even infarct volume.For new vessels to evolve the parenchyma needs to reorganize, that is, making space and providing structures for vessel formation. Matrix metalloproteinases (MMPs) are involved in the degradation and remodelling of the extracellular matrix. Thus, MMPs play an important role in the initial steps of angiogenesis as they degrade the basal lamina for endothelial cell invasion. Unfortunately, this process is a further factor contributing to poststroke edema formation. Blockage of MMP activity has indeed been reported to reduce edema formation showing beneficial effects for stroke outcome.A further pathophysiologic event to be considered in association with angiogenesis also stems from leaky vessels. The degradation of the extracellular matrix during angiogenesis has been correlated with high levels of MMPs, in particular upregulation of MMP-2 and MMP-9.5 But such high levels of MMPs correlate with the event of hemorrhagic transformation after tissue-type plasminogen activator treatment.6 Such increased risk for hemorrhagic transformation has also been reported in cases of intravenous VEGF application for enhancement of angiogenesis.Recently, a new role of angiogenesis after stroke has been discussed.7 These authors noted higher accumulation of macrophages in areas with increased vascular density after stroke. This led to the hypothesis that angiogenesis actually acts as a route for infiltration of macrophages. Although this hypothesis needs further investigation to judge its importance, in this perspective, angiogenesis could actually enhance the proinflammatory state of the parenchyma, further aggravating the neuronal damage.In summary, although angiogenesis may act as a positive and necessary regenerative process after stroke, the endothelial barrier function is severely compromised during the vascular remodelling process. For new vessels to evolve the existing vasculature needs to loosen the endothelial cell connections to allow endothelial sprouting. Essential factors involved in this process are VEGF and MMPs. In parallel to inducing angiogenesis, their expression triggers a cascade of aggravating events: blood brain–barrier injury leads to edema formation, and infarct increase. Increased vascular permeability also increases the risk of hemorrhagic transformation further aggravating stroke outcome. Finally, increased vessel density in the early phase after stroke may also contribute to enhanced inflammatory reaction, further increasing neuronal damage. Thus, in conclusion, the nature of angiogenesis and its beneficial time window, but also the pathophysiologic risk factors need to be critically considered when angiogenesis is expected to demonstrate positive effects in stroke pathology.Sources of FundingThis work was financially supported by grants from the European Union 7th Framework Program: TargetBraIn (HEALTH-F2-2012–279017) and BrainPath (PIAPP-GA-2013–612360).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. This article is Part 2 of a 3-part article. Parts 1 and 3 appear on pages x and x, respectively.Correspondence to Mathias Hoehn, PhD, In-vivo-NMR Laboratory, Max Planck Institute for Metabolism Research, Gleuelerstrasse 50, D-50931 Köln, Germany. 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Iwasawa E, Ichijo M, Ishibashi S and Yokota T (2016) Acute development of collateral circulation and therapeutic prospects in ischemic stroke, Neural Regeneration Research, 10.4103/1673-5374.179033, 11:3, (368), . May 2015Vol 46, Issue 5 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/STROKEAHA.114.007642PMID: 25813195 Manuscript receivedNovember 25, 2014Manuscript acceptedJanuary 9, 2015Originally publishedMarch 26, 2015 Keywordsbrainedemahemorrhageangiogenesismatrix metalloproteinasesvascular endothelial growth factorPDF download Advertisement SubjectsTreatment
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