|Year : 2015 | Volume
| Issue : 1 | Page : 97-103
Cerebrovascular ischemic protection by pre- and post-conditioning
Jeffrey M Gidday
Department of Neurosurgery; Department of Cell Biology and Physiology; Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA
|Date of Submission||01-Apr-2015|
|Date of Acceptance||27-Jul-2015|
|Date of Web Publication||30-Sep-2015|
Jeffrey M Gidday
Department of Neurosurgery, Washington University School of Medicine, Box 8057, St. Louis, Missouri - 63110
Source of Support: None, Conflict of Interest: None
Stroke and cardiac arrest involve injury to all the brain's resident cells and their respective progenitors, including neurons, all glial subtypes, vascular smooth muscle, vascular endothelium, and pericytes, resulting either in the death of the individual or in a lesion that likely manifests as long-term impairments across a number of cognitive and functional domains. Thousands of studies in experimental animals and results from a few clinical trials in humans have demonstrated that the mechanisms responsible for ischemic brain injury can be blocked or slowed by survival-enhancing epigenetic responses induced by "conditioning" the brain with a stress stimulus paradigm before or even after ictus. The resultant reduction in lesion size and functional deficits are often termed endogenous "neuroprotection," but this in fact involves cytoprotective responses on the part of all the aforementioned resident brain cells and the circulating immune cells as well. The present review will summarize findings demonstrating conditioning-induced protection of the cerebral vasculature, that in turn manifests as reductions in vascularly targeted inflammatory responses; less endothelial injury and improvements in structural integrity of the circulation across all levels of organization; enhanced perfusion with less thrombosis; reductions in vascular dysregulation and reactivity impairments; and, over the longer term, more robust angiogenesis and vascular remodeling. Advancing the mechanistic basis for these innately vasculoprotective phenotypes may provide therapeutic targets for limiting cerebral circulatory injury and dysfunction following stroke and cardiac arrest.
Keywords: Cardiac arrest, endothelium, epigenetics, preconditioning, stroke, tolerance
|How to cite this article:|
Gidday JM. Cerebrovascular ischemic protection by pre- and post-conditioning. Brain Circ 2015;1:97-103
| Introduction|| |
The public health burden of stroke in Western society is significant, ranking fourth in mortality and first in morbidity and related cost of care.  Cerebrovascular function is directly and indirectly affected by stroke and cardiac arrest, and as such is an important contributor to these morbidity/mortality statistics. In brief, as a result of many multifactorial mechanisms, cerebral ischemia leads to an inflammatory response characterized, in part, by: The capture and transmigration of circulating leukocytes into brain parenchyma; ,, a breakdown of the blood-brain barrier (BBB); , cerebral blood flow (CBF) changes that are inadequate for the ongoing metabolic demands of the tissue or are inappropriate for moment-to-moment autoregulatory needs; ,, and direct endothelial cell injury or apoptotic death.  Some of these pathological responses continue well into recovery, including inadequate angiogenesis and vascular remodeling. , Thus, cerebrovascular protection, and secondary neuroprotection, resulting from treatments specifically targeted to these vascular dysfunction and injury mechanisms, could significantly improve outcomes from local and global cerebral ischemia. 
Conditioning-based epigenetics represent a unique therapeutic strategy for impacting multiple injury pathways simultaneously, including the aforementioned vascular-specific ones. Conditioning involves the intentional application of a noninjurious physiologic or pharmacologic stimulus or stimulus train before or after stroke (pre- and postconditioning, respectively) with the intention of triggering cell-specific and tissue-wide adaptive changes in gene expression such that, overall, the brain becomes transiently more resistant to ischemia. ,,,, A strong foundation of experimental conditioning studies is present documenting poststroke protective outcomes across all of the aforementioned vascular dysfunction endpoints. These findings are reviewed below, along with their currently understood mechanistic features. For space considerations, few attempts were made herein to specifically identify the details of the physiologic (hypoxia, brief ischemia of the target or distant tissue, heat shock, exercise, electroacupuncture, etc.) or pharmacologic (anesthetics, 3-nitropropionic acid, prolyl hydroxylase inhibitors, resveratrol, herbals/phytochemicals, etc.) stimulus used when mentioning a given outcome. Of the pharmacologic postconditioning studies cited herein, caveats were not advanced regarding whether a given treatment represents a "true" conditioning approach that triggers an adaptive epigenetic response and/or the agent simply exerts direct protective effects on the vasculature and thus is not conceptually different from a more standard pre- or posttreatment paradigm; in most instances, this important distinction has yet to be experimentally addressed. Finally, the experimental stroke model (global, transient focal, permanent focal, chronic hypoperfusion, in vitro cultures, etc.) used for every study cited herein was not necessarily highlighted, as part of a larger effort to promote brevity within a broad and deep review.
| Endothelial Protection|| |
All cell types in the brain likely respond epigenetically to conditioning stimuli, not just neurons. Thus, the respective phenotypes of endothelial cells, smooth muscle cells, and pericytes become transformed into ones that better resist ischemic injury and death. However, direct evidence for this hypothesis is largely lacking, save for endothelial cells. From studies of cultured cerebrovascular endothelial cells, it has been demonstrated that preconditioning protects against simulated ischemia-induced apoptosis secondary to an Akt-mediated activation of the inhibitor-of-apoptosis protein (IAP) survivin  and cellular inhibitor of apoptosis protein-1 (cIAP1).  Other culture studies have provided evidence for protective signaling pathways involving the vascular endothelial growth factor (VEGF)-A and VEGF receptor-2 (VEGFR2)-mediated phosphorylation of the cyclic AMP response element-binding protein (CREB),  and sirtuin (silent mating type information regulation 2 homolog) 1 (S. cerevisiae) (i.e., SIRT1).  Conditioning also protects against glucotoxicity-induced apoptosis in cultured cerebral endothelium,  and correlates with elevated levels of erythropoietin (EPO), endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO), VEGF, and low levels of mitochondrial reactive oxygen species (ROS). The endothelial cell-specific expression of several cytoprotective mediators, e.g., heat shock protein-72 (HSP-72),  and hypoxia-inducible factor-1α (HIF-1α), , documented to increase in conditioned brains or conditioned cultures of cerebral endothelium, may also participate in mediating the enhanced resistance of this specific vascular cell type to ischemic injury.
| Reductions In Postischemic Vascular Inflammation|| |
Inflammation represents a classic example of hormesis, or "the dose makes the poison," with respect to conditioning-induced stroke tolerance. More specifically, while the ischemia-tolerant brain is characterized by reductions in a variety of inflammatory metrics (see below), evidence also suggests that low levels of proinflammatory molecules such as lipopolysaccharide can not only trigger tolerance-promoting signaling cascades when given exogenously, ,,,,, but that the elaboration of endogenous proinflammatory cytokines [tumor necrosis factor-alpha (TNFa), interleukin 1-beta (IL-1β), etc.] and chemokines [C-C motif chemokine ligand 2 (CCL2), etc.] by other conditioning stimuli may also play "nontraditional" roles as essential proximal mediators of such cascades, , including CCL2 elaboration in cerebral microvessels. 
A number of distinct features of postischemic vascular inflammation are reduced or abolished in the stroke-tolerant brain. Specifically, preconditioning not only attenuates the numbers of "activated" neutrophils and other leukocyte subtypes induced by ischemia, but also reduces circulating levels of monocytes, T lymphocytes, and granulocytes.  Cerebral endothelial cell expression levels of the message and/or protein levels for the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1), required to capture and ultimately promote leukocyte transmigration into the ischemic brain, are reduced by conditioning, in both cerebral endothelial cell cultures  and in vivo.,,,,,, In turn, in preconditioned animals, leukocyte rolling along inflamed endothelium is quantitatively reduced,  as is the extent of overall leukocyte diapedesis into the brain parenchyme. ,,,,,,, More specifically, the infiltration of both innate and adaptive immune cells into the ischemic brain is reduced by conditioning,  with the diapedesis of monocytes, macrophages, neutrophils, and T cells reduced, but not that of B cells, the latter of which may actually contribute to neurovascular protection.  The degree to which ischemia induces activation of microglia is lower in pre- and postconditioned brains. ,,, Finally, in postconditioned animals, the extent of peripheral lymphopenia following stroke is attenuated in postconditioned animals,  as is the extent of monocyte activation. 
Lower levels of proinflammatory cytokine and chemokine elaboration into blood and extracellular spaces following stroke may account for the overall attenuation of these various postischemic inflammation metrics in conditioned animals. ,,, This, in turn, may result from decreases in the overall expression levels of proinflammatory transcription factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB).  Conversely, enhanced expression of survival-enhancing transcription factors such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2)  and HIF-1α may participate in mediating this phenotype. The latter can drive reported increases in cerebral endothelial cell levels of heme oxygenase-1 (HO-1),  EPO,  VEGF,  and other molecules with known anti-inflammatory effects.
| Improvements In Postischemic Bbb Integrity|| |
As with other vascular injury endpoints measured in the postischemic brain, improvements in BBB integrity, manifested as reductions in tracer leakage or tissue water content, represent a widely reported vasculoprotective phenotype in conditioned animals, independent of the variety of physiologic and pharmacologic pre- and postconditioning stimuli used, and the ischemic model. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Similar findings regarding barrier resistance have been reported using in vitro models of the BBB. , The extent of hemorrhagic transformation following focal embolic stroke is also reduced in conditioned animals. 
Mechanistically, reductions in ischemia-induced disruptions in the BBB likely result from molecular changes regulating vascular permeability at a number of levels of vascular organization, including preservation of tight junction protein expression/localization, ,,,,, upregulation of barrier-strengthening integrins on microvessels,  minimization of filamentous actin (F-actin) stress fiber formation,  aquaporin channel modulation, , and reductions in the extent of elaboration of inducible nitric oxide synthase (iNOS)  and matrix metallopeptidase 9 (MMP9). ,,,, In turn, these changes may be driven by conditioning-induced reductions in endothelial NFkB and ROS,  and/or increases in endothelial sphingosine-1-phosphate (S1P) levels, , 70 kilodalton heat shock protein (Hsp-70) expression,  type-1 interferon (IFN),  insulin-like growth factor 1 (IGF-1),  NO production via eNOS, ,,,,,, and/or mitochondrial membrane depolarization. 
| Augmented Postischemic Perfusion and Vascular Reactivity|| |
Periinfarct CBF is reduced in the early hours following focal stroke, and a period of hypoperfusion follows global ischemia as well; both of these "insults to injury" likely contribute to the ultimate extent of ischemic damage so manifested. While in conditioned animals subjected to transient focal stroke the magnitude of the resultant reactive hyperemia is blunted by postconditioning,  a more general, but not universal,  finding - whether measured as absolute or relative flows - is that levels of postischemic periinfarct CBF, normally depressed in the early hours to days following ischemia, run higher. ,,,,, Moreover, these studies showed that regions of preserved perfusion in tolerant animals were associated with regions of tissue sparing,  that increases in CBF were paralleled by increases in oxygen consumption,  and that the timely reperfusion of the penumbra is critical to conditioning-induced protection in focal stroke.  At longer times of recovery following focal stroke, lower levels of overall CBF may characterize the tolerant brain secondary to a reduced baseline metabolic demand and intact flow-metabolism coupling. ,
During recovery following global ischemia, normally characterized by a state of hypoperfusion, CBF is enhanced in most brain regions studied in animals that were conditioned; ,,, this makes it difficult to unequivocally conclude that enhanced perfusion in selectively vulnerable regions such as the CA1 hippocampal subfield was required for the neuronal protection observed in these regions.  Interestingly, conditioning also attenuates the extent of reactive hyperemia immediately following the period of ischemia. , In a mouse model of vascular cognitive impairment secondary to cerebral hypoperfusion, postischemic CBF levels were higher in animals receiving repetitive remote postconditioning;  moreover, the perfusion improvement was sustained at 1 month, well after discontinuing the postconditioning stimulus.
Of note, preconditioning may actually reduce the extent of CBF reduction during the period of ischemia itself, given findings in newborn  and adult ,, rodents; however, this is not a widespread finding, with others reporting no effect of immediate  or advanced preconditioning ,, on intraischemic CBF. Finally, in mice with subarachnoid hemorrhage (SAH), preconditioning  and postconditioning  reduce the extent of large-artery vasospasm; in humans with SAH, transcranial Doppler measures suggestive of increased blood flow were recorded during periods of remote conditioning. 
Ischemia-induced impairments in vascular reactivity are also abrogated by conditioning. For example, in vivo studies have revealed the prevention of ischemia-impaired dilatory responses of pial arterioles to whisker stimulation, topical acetylcholine, and hypercapnia.  Moreover, in isolated vessel preparations obtained from conditioned adult animals subjected to stroke, , and from neonates subjected to intrauterine asphyxia,  endothelium-dependent dilations to acetylcholine were also restored. In a model of SAH-induced vasospasm, preconditioning with hypoxia  or postconditioning with isoflurane  also prevented impairments in pial arteriolar reactivity to endothelium-dependent dilators. Collectively, these findings indicate that conditioning exerts direct protective effects on both cerebral resistance vessels and larger arteries that allow for appropriate autoregulatory responses.
The mechanisms by which perfusion is generally augmented in the ischemic and postischemic brain of conditioned animals is surely multifactorial, but few studies have directly attempted to elucidate the regulatory steps affected by conditioning; a similar summary applies to understanding how vascular reactivity remains intact in a conditioned brain. A number of lines of evidence support the concept that eNOS-derived NO levels are higher in conditioned animals, perhaps as a result of a reduction in the extent of eNOS uncoupling,  resulting in increases in postischemic tissue perfusion. , Indeed, reductions in eNOS expression and activity levels, as well as NO availability, resulting from SAH were ameliorated by preconditioning,  consistent with the loss of preconditioning-induced protection against SAH-induced vasospasm in eNOS-mull mice.  There is also good causal evidence for the direct involvement of iNOS-derived NO,  or the indirect participation of iNOS-derived NO through its formation of peroxynitrite via reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide radical,  in maintaining both CBF and the integrity of endothelium-dependent responsivity. The expression of HIF-1α genes from endothelial cells was demonstrated-by using endothelial cell-specific HIF-1α knockout mice-as critical to the amelioration of vasospasm in the setting of isoflurane postconditioning.  Lower serum levels of the vasoconstrictor endothelin have been measured 24 h following global  and focal  ischemia in mice and rats, respectively, temporally coincident with the higher postischemic CBF recorded in these models. Perfusion improvements may also be forthcoming as a result of reductions in thrombosis. As evidence of this possibility, decreased levels of thrombomodulin and von Willebrand factor in plasma characterize the tolerant brain;  microvascular fibrinogen immunostaining in the cortex of mouse brains subjected to SAH is reduced by postconditioning;  and in humans with large vessel strokes, earlier recanalization is noted following intravenous thrombolysis in a physical exercise cohort relative to sedentary controls.  In fact, remote conditioning in humans with SAH resulted in prolongation of coagulation times. 
| Enhanced Postischemic Angiogenesis and Vascular Remodeling|| |
That the conditioned brain would exhibit an enhanced angiogenic response following stroke is a phenotype expected of the neurovascular plasticity underlying ischemic tolerance. Indeed, angiogenesis genes are upregulated in the neonatal rat brain in response to preconditioning, and the postischemic reduction in capillary density in this model is ameliorated,  or reversed to levels above baseline, , in conditioned animals. In the adult brain, a conditioning-induced increase in capillary density occurs in the penumbra 3 days after focal stroke, , but other studies have found no changes in this angiogenesis metric.  Several different integrins are upregulated in the cerebrovasculature in response to exercise preconditioning, and their expression is preserved following stroke.  Interestingly, postischemic angiogenesis is enhanced following stem cell therapy if the stem cells themselves are conditioned. ,
With respect to the mechanisms underlying this phenotype, in many models of conditioning-induced cerebrovascular protection, increases in VEGF are measured during ischemic recovery, ,,,, which, depending on the temporal pattern of its elaboration, may counteract to some extent conditioning-induced reductions in BBB permeability in exchange for it acting as a mitogen for vasculogenesis. Increases in VEGF are also implicated as mediating the conditioning-induced increase in intraischemic CBF.  Also correlated with an enhanced angiogenesis phenotype are conditioning-associated elevations in the expression of angiopoietin,  insulin-like growth factor 1 (IGF-1),  and angiogenin.  Delayed elevations in MMP9 in conditioned animals may serve to facilitate angiogenesis during the more protracted period of postischemic recovery. 
| Mechanisms and Therapeutic Potential|| |
Predictably, the mechanisms by which conditioning approaches protect the cerebrovasculature across the various aforementioned phenotypes, many of which have already been discussed, are as complex and multifactorial as those responsible for the different manifestations of ischemic vascular injury themselves. Moreover, there are many "levels" to interrogate when considering therapeutic targets: Identifying the proximal players signaling the epigenetic response; elucidating increases and decreases in the expression of the specific genes affected; and characterizing the spatiotemporal features of the new vasculoprotective phenotype. Advances in cerebrovascular proteomics  may help for the latter, but clinically viable therapeutics are more likely to derive from drugs that activate more proximal signaling pathways that are somehow conserved, as reflected by their responsivity to a myriad of conditioning stimuli.
Many studies have focused on NO, primarily that derived from eNOS, ,,,,,,, as a key signaling intermediate between the conditioning stimulus and the resultant change in gene expression. However, in other investigations, evidence has been provided that the NO signal derives from iNOS. , Making causal evidence difficult to obtain with respect to NO's role as a proximal mediator is the fact that NO also acts as an effector of many vasculoprotective phenotypes, in part by countering ischemia-induced reductions in NO bioavailability.  Free radical species may also serve as key signaling intermediates in establishing vasculoprotective phenotypes. ,,
The cerebrovascular endothelium is strategically positioned to serve in a sentry-like capacity to transduce changes in the levels of blood-borne conditioning stimuli to signals that surrounding neurons and glia "understand" as stimuli for adaptive epigenetic change. This is particularly true for remote conditioning paradigms,  but also for systemically based conditioning stimuli such as whole-body hypoxia and lipopolysachharides (LPS), among others. The mechanisms that regulate each step of such an endothelial cell-based paracrine signaling pathway are surely complex, and have yet to be elucidated.
| Conclusions|| |
Conditioning-based treatments for stroke and cardiac arrest exert myriad protective effects at all levels of cerebral macro- and microcirculatory organization that are manifested, in turn, as reductions in cerebrovascular injury and dysfunction. Improvements in neuronal and glial viability may represent secondary benefits that contribute to the overall extent of protection observed in the conditioned brain. A better understanding of the molecular, genetic, and epigenetic bases of the vasculoprotective responses triggered by conditioning stimuli could facilitate the development of therapeutics that robustly impact stroke morbidity and mortality.
Supported by National Institutes of Health (NIH) R01EY018607.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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