Elsevier

Progress in Neurobiology

Volume 115, April 2014, Pages 138-156
Progress in Neurobiology

Vascular remodeling after ischemic stroke: Mechanisms and therapeutic potentials

https://doi.org/10.1016/j.pneurobio.2013.11.004Get rights and content

Highlights

  • Distinct mechanisms underlying arteriogenesis and angiogenesis are delineated.

  • Technology in detecting each vascular remodeling process.

  • Clinical and preclinical implications of arteriogenesis and angiogenesis.

  • Potential therapies in promoting vascular remodeling including those in trials.

Abstract

The brain vasculature has been increasingly recognized as a key player that directs brain development, regulates homeostasis, and contributes to pathological processes. Following ischemic stroke, the reduction of blood flow elicits a cascade of changes and leads to vascular remodeling. However, the temporal profile of vascular changes after stroke is not well understood. Growing evidence suggests that the early phase of cerebral blood volume (CBV) increase is likely due to the improvement in collateral flow, also known as arteriogenesis, whereas the late phase of CBV increase is attributed to the surge of angiogenesis. Arteriogenesis is triggered by shear fluid stress followed by activation of endothelium and inflammatory processes, while angiogenesis induces a number of pro-angiogenic factors and circulating endothelial progenitor cells (EPCs). The status of collaterals in acute stroke has been shown to have several prognostic implications, while the causal relationship between angiogenesis and improved functional recovery has yet to be established in patients. A number of interventions aimed at enhancing cerebral blood flow including increasing collateral recruitment are under clinical investigation. Transplantation of EPCs to improve angiogenesis is also underway. Knowledge in the underlying physiological mechanisms for improved arteriogenesis and angiogenesis shall lead to more effective therapies for ischemic stroke.

Section snippets

Collateral circulation and arteriogenesis as the new therapeutic targets of cerebral ischemia

Stroke or cerebral ischemia leads to cerebrovascular adaptations both acutely and chronically. During acute flow obstruction, some parts of the brain tissue suffer from ischemia while others are sustained by collateral flow through pre-existing anastomoses. Collateral circulation refers to the supplemental network of vessels that compensate blood flow and offset the adverse effect of ischemia (Kucinski et al., 2003, Liebeskind, 2003, Liebeskind, 2005a, Liebeskind, 2005b, Shuaib et al., 2011b,

The role of angiogenesis in cerebrovascular diseases and therapy

Angiogenesis is a tightly controlled process in the central nervous system (CNS). In cancer, inhibition of angiogenesis is an effective therapeutic strategy for treating solid tumors. Conversely, promoting focal angiogenesis could provide an opportunity for improving outcomes of ischemia-related diseases. Understanding the molecular and cellular mechanisms by which angiogenesis occurs appears promising to yield potential therapeutic targets for ischemic brain diseases. However, numerous

Conclusions and perspectives

Both arteriogenesis and angiogenesis are tightly controlled processes under physiological and pathological conditions. Arteriogenesis is triggered by mechanical force, while angiogenesis is induced by a hypoxic environment. Strategies to increase collateral flow have been shown to hold promise in improving the outcome of acute stroke and recanalization therapies in stroke patients. Experimental studies suggest that enhancing angiogenesis is linked to an improved recovery of function and brain

Acknowledgements

This work was supported by NIH grant R01 NS071050 (J.L.), AHA EIA 0940065N (J.L.), China 973 Program 2010CB834306 and 2011CB504405 (G.Y.Y. and W.Y.), NSFC 81070939 (G.Y.Y.) and U1232205 (G.Y.Y.).

References (272)

  • M.D. Ginsberg

    Neuroprotection for ischemic stroke: past, present and future

    Neuropharmacology

    (2008)
  • B. Halliwell

    Albumin – an important extracellular antioxidant?

    Biochem. Pharmacol.

    (1988)
  • Y. Akamatsu et al.

    Impaired acute collateral flow dynamics following experimental stroke in Type 2 diabetic mice

    Stroke

    (2013)
  • Y. Akamatsu et al.

    Consistent focal cerebral ischemia without posterior cerebral artery occlusion and its real-time monitoring in an intraluminal suture model in mice

    J. Neurosurg.

    (2012)
  • B.J. Alpers et al.

    Anatomical studies of the circle of Willis in normal brain

    AMA Arch. Neurol. Psychiatry

    (1959)
  • S. Anand et al.

    MicroRNA-132-mediated loss of p120RasGAP activates the endothelium to facilitate pathological angiogenesis

    Nat. Med.

    (2010)
  • K. Arai et al.

    Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke

    FASEB J.

    (2009)
  • G.A. Armitage et al.

    Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke

    J. Cereb. Blood Flow Metab.

    (2010)
  • A. Armulik et al.

    Pericytes regulate the blood–brain barrier

    Nature

    (2010)
  • M. Arras et al.

    Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb

    J. Clin. Invest.

    (1998)
  • T. Asahara et al.

    Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo

    Circulation

    (1995)
  • S. Aslanyan et al.

    Effect of blood pressure during the acute period of ischemic stroke on stroke outcome: a tertiary analysis of the GAIN International Trial

    Stroke

    (2003)
  • H.G. Augustin et al.

    Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system

    Nat. Rev. Mol. Cell Biol.

    (2009)
  • K. Ayajiki et al.

    Effects of capsaicin and nitric oxide synthase inhibitor on increase in cerebral blood flow induced by sensory and parasympathetic nerve stimulation in the rat

    J. Appl. Physiol.

    (2005)
  • C. Ayata et al.

    Laser speckle flowmetry for the study of cerebrovascular physiology in normal and ischemic mouse cortex

    J. Cereb. Blood Flow Metab.

    (2004)
  • C. Ayata et al.

    Pronounced hypoperfusion during spreading depression in mouse cortex

    J. Cereb. Blood Flow Metab.

    (2004)
  • P. Ballabh

    Intraventricular hemorrhage in premature infants: mechanism of disease

    Pediatr. Res.

    (2010)
  • S. Banai et al.

    Angiogenic-induced enhancement of collateral blood flow to ischemic myocardium by vascular endothelial growth factor in dogs

    Circulation

    (1994)
  • O.Y. Bang et al.

    Impact of collateral flow on tissue fate in acute ischaemic stroke

    J. Neurol. Neurosurg. Psychiatry

    (2008)
  • O.Y. Bang et al.

    Collateral flow predicts response to endovascular therapy for acute ischemic stroke

    Stroke

    (2011)
  • O.Y. Bang et al.

    Collateral flow averts hemorrhagic transformation after endovascular therapy for acute ischemic stroke

    Stroke

    (2011)
  • A. Bar-Shir et al.

    Late stimulation of the sphenopalatine-ganglion in ischemic rats: improvement in N-acetyl-aspartate levels and diffusion weighted imaging characteristics as seen by MR

    J. Magn. Reson. Imaging

    (2010)
  • A. Beenken et al.

    The FGF family: biology, pathophysiology and therapy

    Nat. Rev. Drug Discov.

    (2009)
  • L. Belayev et al.

    Effect of delayed albumin hemodilution on infarction volume and brain edema after transient middle cerebral artery occlusion in rats

    J. Neurosurg.

    (1997)
  • L. Belayev et al.

    Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses

    Stroke

    (2002)
  • L. Belayev et al.

    Diffusion-weighted magnetic resonance imaging confirms marked neuroprotective efficacy of albumin therapy in focal cerebral ischemia

    Stroke

    (1998)
  • C.E. Bergmann et al.

    Arteriogenesis depends on circulating monocytes and macrophage accumulation and is severely depressed in op/op mice

    J. Leukoc. Biol.

    (2006)
  • D.A. Boas et al.

    Laser speckle contrast imaging in biomedical optics

    J. Biomed. Opt.

    (2010)
  • M.W. Bobbie et al.

    Reduced connexin 43 expression and its effect on the development of vascular lesions in retinas of diabetic mice

    Invest. Ophthalmol. Vis. Sci.

    (2010)
  • T. Boehm et al.

    Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance

    Nature

    (1997)
  • T. Bogoslovsky et al.

    Induced hypertension for the treatment of acute MCA occlusion beyond the thrombolysis window: case report

    BMC Neurol.

    (2006)
  • P. Bose et al.

    Bevacizumab in hereditary hemorrhagic telangiectasia

    N. Engl. J. Med.

    (2009)
  • A. Braun et al.

    Paucity of pericytes in germinal matrix vasculature of premature infants

    J. Neurosci.

    (2007)
  • A.M. Bremer et al.

    Ischemic cerebral edema in primates: effects of acetazolamide, phenytoin, sorbitol, dexamethasone, and methylprednisolone on brain water and electrolytes

    Neurosurgery

    (1980)
  • M. Brozici et al.

    Anatomy and functionality of leptomeningeal anastomoses: a review

    Stroke

    (2003)
  • I. Buschmann et al.

    Influence of inflammatory cytokines on arteriogenesis

    Microcirculation

    (2003)
  • J. Bussmann et al.

    Arterial–venous network formation during brain vascularization involves hemodynamic regulation of chemokine signaling

    Development

    (2011)
  • R. Cao et al.

    Angiogenic synergism, vascular stability and improvement of hind-limb ischemia by a combination of PDGF-BB and FGF-2

    Nat. Med.

    (2003)
  • B.J. Capoccia et al.

    Recruitment of the inflammatory subset of monocytes to sites of ischemia induces angiogenesis in a monocyte chemoattractant protein-1-dependent fashion

    J. Leukoc. Biol.

    (2008)
  • P. Carmeliet

    Angiogenesis in health and disease

    Nat. Med.

    (2003)
  • Cited by (259)

    View all citing articles on Scopus
    1

    These authors contributed equally to this work.

    View full text