Cerebral collateral flow defines topography and evolution of molecular penumbra in experimental ischemic stroke
Introduction
Intracranial collateral circulation represents a multiple-level subsidiary vascular network which is dynamically recruited after occlusion of cerebral arteries to provide a source of residual blood flow (Liebeskind, 2003).
In both humans and rodents, a significant supply of collateral flow after middle cerebral artery (MCA) occlusion is provided by the circle of Willis through the anterior cerebral artery (ACA) and the leptomeningeal anastomoses between the cortical branches of ACA and MCA. However, a significant degree of inter-individual variability exists in the functional performance of intracranial collaterals under ischemic conditions in humans (Qureshi et al., 2008, Liu et al., 2011) and rodents (Armitage et al., 2010, Riva et al., 2012).
Cerebral collateral flow is emerging as a powerful determinant of functional and tissue outcome in unselected ischemic stroke patients (Maas et al., 2009, Menon et al., 2011) and in stroke patients treated with intravenous rtPA (Brunner et al., 2012, Miteff et al., 2009) or endovascular recanalization (Bang et al., 2011, Bang et al., 2008).
For these reasons, an in-depth understanding of the physiology, adaptive response and modulation of intracranial collateral circulation is of foremost importance for acute stroke pathophysiology and therapy.
Ischemic penumbra was originally defined as “tissue at risk”, which has been made functionally silent and metabolically metastable by ischemic injury but still has the potential for full recovery if reperfusion is timely achieved (Branston et al., 1974, Hossmann, 1994, Baron, 1999). The concept of ischemic penumbra is gradually evolving, after pre-clinical and clinical studies showed a heterogeneous and variable pattern of perfusion deficit, molecular response, topographical distribution and evolution of the penumbra in relation to the ischemic core (del Zoppo et al., 2011, Manning et al., 2014).
HSP70 is the major inducible heat shock protein (Sharp et al., 2000), whose expression after focal cerebral ischemia reflects an endogenous cell response to injury. The neuronal expression of HSP70 is considered as a molecularly defined penumbra, where injured neurons have activated endogenous pathways for protein renaturation and protection against further ischemia.
In the present study, we investigated the relationship between intracranial collateral flow during transient MCA occlusion and the development of molecular penumbra and ischemic infarct after 24 h. The hemodynamic monitoring of central and peripheral MCA territories was analyzed in terms of perfusion deficit and biosignal fluctuation. Hemodynamic data were correlated with the corresponding areas of molecular penumbra, infarct volume and functional deficit.
Section snippets
Study design
The experimental protocol was approved by the Committee on Animal Care of the University of Milano Bicocca, in accordance with the national guidelines on the use of laboratory animals (D.L. 116/1992) and the European Union Directive for animal experiments (2010/63/EU), under project license from the Italian Ministry of Health.
A group of consecutive animals undergoing successful MCA occlusion (see below) were used to explore the effect of cerebral collateral flow on molecular penumbra. Cerebral
Multi-site cerebral perfusion monitoring during MCA occlusion
Hemodynamic monitoring with two LD probes was performed during transient MCA occlusion, as shown in Fig. 1. The position of the probes was decided according to the rat cerebral vascular territories and verified by gelatin-ink perfusion experiments (Fig. 1A). Probe 1 (bregma − 1 mm, 5 mm from midline) was positioned within the central MCA territory, while Probe 2 (bregma + 2 mm, 2 mm from midline) was positioned in the borderzone territory between the cortical branches of ACA and MCA to monitor
Discussion
The functional performance of intracranial collaterals is crucially involved in the pathophysiology of acute ischemic stroke (Liebeskind, 2012). Functionally active cerebral collaterals have been associated with reduced penumbra loss (Jung et al., 2013) and better outcomes (Cortijo et al., 2014) in acute stroke patients, even with delayed reperfusion.
Therapeutic modulation of cerebral collateral flow is being proposed (Shuaib et al., 2011) and may be used for widening the therapeutic window for
Conclusions
The degree of cerebral collateral perfusion inversely correlated with both ischemic core and molecular penumbra during transient proximal MCA occlusion. Our findings prompt the development of collateral therapeutics to provide tissue-saving strategies in the hyper-acute phase of ischemic stroke prior to recanalization therapy.
Conflict of interest
The authors declare no conflict of interest.
The following are the supplementary data related to this article.
Acknowledgments
We thank Dr. Virginia Rodriguez Menendez for the technical assistance with immunohistochemistry and Miss Elena Pirovano for the figure preparation. This study was supported by the Italian Ministry of University and Research (MIUR, FAR12-01-138-2002100) and Université Lyon 1. These funding sources were not involved in the study design, collection, analysis and interpretation of data, writing of the report or decision to submit the present article for publication.
References (36)
- et al.
Relationship between the cortical evoked potential and local cortical blood flow following acute middle cerebral artery occlusion in the baboon
Exp. Neurol.
(1974) - et al.
MRI profile and response to endovascular reperfusion after stroke (DEFUSE 2): a prospective cohort study
Lancet Neurol.
(2012) - et al.
Hyperintense vessels on FLAIR: a useful non-invasive method for assessing intracerebral collaterals
Eur. J. Radiol.
(2011) - et al.
Hemodynamic monitoring of intracranial collateral flow predicts tissue and functional outcome in experimental ischemic stroke
Exp. Neurol.
(2012) - et al.
Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target [Review]
Lancet Neurol.
(2011) - et al.
Laser speckle contrast imaging of collateral blood flow during acute ischemic stroke
J. Cereb. Blood Flow Metab.
(2010) - et al.
Impact of collateral flow on tissue fate in acute ischaemic stroke
J. Neurol. Neurosurg. Psychiatry
(2008) - et al.
Collateral flow predicts response to endovascular therapy for acute ischemic stroke
Stroke
(2011) Mapping the ischaemic penumbra with PET: implications for acute stroke treatment [Review]
Cerebrovasc. Dis.
(1999)- et al.
Optimized system for cerebral perfusion monitoring in the rat stroke model of intraluminal middle cerebral artery occlusion
J. Vis. Exp.
(2013)
Impact of collateral circulation on early outcome and risk of hemorrhagic complications after systemic thrombolysis
Int. J. Stroke
Relative cerebral blood volume as a marker of durable tissue-at-risk viability in hyperacute ischemic stroke
Stroke
Heterogeneity in the penumbra
J. Cereb. Blood Flow Metab.
Multimodal MRI of experimental stroke
Transl. Stroke Res.
Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation
Stroke
The ischemic penumbra: correlates in imaging and implications for treatment of ischemic stroke. The Johann Jacob Wepfer Award 2011
Cerebrovasc. Dis.
Viability thresholds and the penumbra of focal ischemia
Ann. Neurol.
Relevance of laser Doppler and laser speckle techniques for assessing vascular function: state of the art and future trends
IEEE Trans. Biomed. Eng.
Cited by (18)
Emergent Uric Acid Treatment is Synergistic with Mechanical Recanalization in Improving Stroke Outcomes in Male and Female Rats
2018, NeuroscienceCitation Excerpt :Our results point to a specific superior protective effect of UA in postischemic hyperperfused rats, probably related with its ability to reduce the exacerbated oxidative stress, and in line with previously reported higher neuroprotective effects of the antioxidant vitamin-E analog CR-6 (Pérez-Asensio et al., 2010) and UA (Onetti et al., 2015) in hyperperfused male Sprague–Dawley rats. On the other hand, the functional performance of intracranial collateral circulation is involved in the pathophysiology of acute ischemic stroke, as assessed in the rat stroke model used in the present study (Beretta et al., 2015). In the clinical arena, UA therapy may prevent early ischemic worsening after acute stroke in thrombolysed patients.
Temporal remodeling of pial collaterals and functional deficits in a murine model of ischemic stroke
2018, Journal of Neuroscience MethodsCitation Excerpt :This steep pressure gradient causes fluid shear stress to activate the endothelium, invoking a cascade of events (Buschmann et al., 2003; Heil et al., 2006; Toriumi et al., 2009) that leads to the production of cytokines, growth factors and proteases which mediate the enlargement of the collateral vessels (Heil et al., 2002; Schaper and Scholz, 2003; Cai and Schaper, 2008; Li et al., 2016). Enhancement of retrograde cerebral blood flow through remodeled collateral vessels into the territory of the occluded artery mitigates cellular damage and helps maintain tissue preservation (Crisostomo et al., 1993; Beretta et al., 2015; Liu et al., 2015; Winship, 2015; Cuccione et al., 2016; van Seeters et al., 2016; Beretta et al., 2017). Thus, enhancing collateral growth and remodeling has become an attractive target for therapeutic intervention in patients suffering from an ischemic attack (Schierling et al., 2011; Chen et al., 2014; Nishijima et al., 2015).
Understanding the neurovascular unit at multiple scales: Advantages and limitations of multi-photon and functional ultrasound imaging
2017, Advanced Drug Delivery ReviewsCitation Excerpt :Owing to the limited spatial and temporal resolutions, the LDF applications used to functionally assess the cortical activity remain weak, but owing to the small size of the device, the LDF modality can be easily combined with electrical recordings [88]. However, the LDF plays a major role in following ischemia in pre-clinical studies [89,90] and is commonly used in various intraoperative clinical investigations [91]. Laser speckle contrast imaging (LSCI) is based on detecting speckle contrasts induced by RBCs.
Ischemic postconditioning in cerebral ischemia: Differences between the immature and mature brain?
2015, International Journal of Developmental NeuroscienceCitation Excerpt :In the adult rat (in a model of transient MCA occlusion), good collateral flow during MCA occlusion provides complete protection from ischemic injury in variable areas of the cortex and striatum, if reperfusion is achieved. Conversely, poor collateral status is associated with a greater extent of both ischemic core and penumbra (Beretta et al., 2015). Maps of blood flow on the surface of the frontoparietal cortex (using laser speckle contrast imaging) and measures of speckle contrast in multiple regions of interest (ROI) indicate that partial blood flow in branches of the MCA is maintained through anastomoses the develop between distal segments of the ACA and MCA during thromboembolic MCAo both in the adult rat (Armitage et al., 2010) and in the immature rat (Leger et al., 2013).
Head down tilt 15° to preserve salvageable brain tissue in acute ischemic stroke: A pre-clinical pooled analysis, with focus on cerebral hemodynamics
2023, European Journal of Neuroscience
- 1
These authors equally contributed to this work.