Perivascular Macrophages Mediate Microvasospasms After Experimental Subarachnoid Hemorrhage
Abstract
BACKGROUND:
Subarachnoid hemorrhage (SAH) is characterized by acute and delayed reductions of cerebral blood flow (CBF) caused, among others, by spasms of cerebral arteries and arterioles. Recently, the inactivation of perivascular macrophages (PVM) has been demonstrated to improve neurological outcomes after experimental SAH, but the underlying mechanisms of protection remain unclear. The aim of our exploratory study was, therefore, to investigate the role of PVM in the formation of acute microvasospasms after experimental SAH.
METHODS:
PVMs were depleted in 8- to 10-week-old male C57BL/6 mice (n=8/group) by intracerebroventricular application of clodronate-loaded liposomes and compared with mice with vehicle liposome injections. Seven days later, SAH was induced by filament perforation under continuous monitoring of CBF and intracranial pressure. Results were compared with sham-operated animals and animals who underwent SAH induction but no liposome injection (n=4/group each). Six hours after SAH induction or sham surgery, numbers of microvasospasms per volume of interest and % of affected pial and penetrating arterioles were examined in 9 standardized regions of interest per animal by in vivo 2-photon microscopy. Depletion of PVMs was proven by quantification of PVMs/mm3 identified by immunohistochemical staining for CD206 and Collagen IV. Statistical significance was tested with t tests for parametric data and Mann-Whitney U test for nonparametric data.
RESULTS:
PVMs were located around pial and intraparenchymal arterioles and were effectively depleted by clodronate from 671±28 to 46±14 PVMs/mm3 (P<0.001). After SAH, microvasospasms was observed in pial arteries and penetrating and precapillary arterioles and were accompanied by an increase to 1405±142 PVMs/mm3. PVM depletion significantly reduced the number of microvasospasms from 9 IQR 5 to 3 IQR 3 (P<0.001).
CONCLUSIONS:
Our results suggest that PVMs contribute to the formation of microvasospasms after experimental SAH.
Graphical Abstract
Subarachnoid hemorrhage (SAH) is a severe subtype of stroke with a high mortality and morbidity resulting in a high socioeconomic burden.1–3
In most cases, an intracranial aneurysm ruptures and blood enters the subarachnoid space, resulting in a rapid increase of intracranial pressure and—subsequently—global ischemia, often fatal within minutes. Although interventional and microsurgical techniques are advanced and allow a safe and efficient occlusion of aneurysms to prevent rebleeding, mortality after SAH is high and many patients who survive the initial ictus still suffer from significant morbidity.1
Major features associated with adverse outcome after SAH include early and delayed cerebral ischemia.2 Advanced imaging in patients and after experimental SAH show severe cortical hypoperfusion despite normal cerebral perfusion pressure within hours after aneurysm rupture.4,5 Spasms of pial and penetrating arterioles (microvasospasms) have been demonstrated to be associated with acute cortical hypoperfusion. Options to treat microvasospasms are not available yet, since the mechanisms involved in the formation of microvasospasms are not fully understood.6–8
Recently, Wan et al9 demonstrated that depletion of perivascular macrophages (PVMs) after experimental SAH improves neurological outcome and reduces perivascular inflammation. Since we observed in previous studies that degradation of blood products resulted in the reduction of microvasospasms, we hypothesize that PVMs may be critically involved in the formation of microvasospasms.
In the current study, we therefore used mice depleted of PVMs and visualized pial and penetrating arterioles in vivo by 2-photon microscopy to investigate whether these cells are involved in the formation of microvasospasms after SAH.
METHODS
The authors declare that all supporting data are available within the article and its Supplemental Material.
Animals and Experimental Groups
All procedures on animals, group size calculations, and statistical methods were approved by the Government of Upper Bavaria. The results of the study are reported in accordance with the Animal Research: Reporting of In Vivo Experiments guidelines. Eight- to 10-week-old male C57BL/6 mice (Jackson Laboratory, Bar Harbor) were used for all experiments. We investigated 4 different groups: (1) SAH (n=4) animals without intrathecal injection, (2) Sham (n=4) operated animals, treated with the same protocol except for middle cerebral artery perforation, (3) SAH+Vehicle (n=8), and (4) SAH+clodronate (n=8; Figure S1; Table S1)
All experiments were performed in a strictly randomized and blinded manner, that is, all investigators were unaware of the status of the mice until all experiments were performed and all data was analyzed.
Depletion of PVMs
Intrathecally injected liposomes loaded with clodronate (Liposoma, the Netherlands), a substance which induces apoptosis once taken up by cells, were used to deplete PVMs 7 days before SAH (Figure 1A). Liposomes without clodronate served as vehicle control. For intrathecal injection, animals were anesthetized, fixed in a stereotactic frame (Foehr Medical Instruments, Germany), and the atlanto-occipital membrane covering the cisterna magna was exposed. A custom-made glass capillary and a microsyringe pump (World Precision instruments) were used to inject 10 µL of liposomes into the cisterna magna at a rate of 3 µL/minute.
Induction of Subarachnoid Hemorrhage
SAH and sham surgery were performed as previously described.7,10 Briefly, mice were anesthetized with a mixture of 0.05 mg/kg fentanyl (Janssen-Cilac, Neuss, Germany), 0.5 mg/kg medetomidine (Pfizer) and 5 mg/kg midazolam (Braun, Germany), intubated, and mechanically ventilated. Core body temperature, pO2, pCO2, mean arterial blood pressure, oxygen saturation, cerebral blood flow, and intracranial pressure were continuously monitored during surgery (Table S2). The Circle of Willis was perforated at the outlet of the left middle cerebral artery with an intravascular filament advanced via the common carotid artery. For sham surgery, the filament was inserted and not advanced far enough to induce perforation. Monitoring was continued for 20 minutes after SAH induction. Anesthesia was then antagonized by subcutaneous injection of 1.2 mg/kg naloxone (Actavis, Ireland), 0.5 mg/kg flumazenil (Inresa, Germany), and 2.5 mg/kg atipamezole (Pfizer).
Two-Photon Microscopy
In vivo imaging was performed with a LSM 7 microscope (Zeiss, Germany), equipped with a Li:Ti laser (Chameleon, Coherent), 6 hours after SAH/sham surgery (Figure 1A). Animals were anesthetized as described above and received a femoral artery catheter. A thinned skull window was prepared above the left hemisphere as previously described.7 Nine random 500×500 µm regions of interest were imaged to a depth of 250 µm (Figure 1B) 6 hours after SAH using a 20× objective (Zeiss, Germany). Animals were continuously monitored for end-expiratory pCO2, body temperature, heart rate, and peripheral oxygen saturation during imaging. To visualize the microcirculation, 100 µL fluoresceinisothiocyanate dextran (0.5% in saline, Sigma-Aldrich) was applied by intraarterial injection.
Histological Analysis and Quantification
After in vivo imaging mice were fixed with 4% paraformaldehyde by intracardial perfusion and 50 µm free-floating coronal brain sections were collected. PVMs were labeled with a CD206+ antibody (BIO-RAD, 1:100). The vasculature was stained with Collagen IV (Abcam, 1:100). As secondary antibodies Donkey Anti-Rat IgG (Abcam, 1:200) and Donkey Anti-Rabbit IgG (Jackson, 1:200) were used. Slices were incubated with the primary antibodies for 3 days at 4 °C and with the secondary antibodies for 2 days at 4 °C. Cell nuclei were labeled by DAPI (1 mg/mL, 1:1000, Vector Labs). PVMs were defined by positive staining with CD206 and direct contact to a vessel. Meningeal macrophages were defined as CD206+ meningeal cells without vascular contact. Sections were imaged by confocal microscopy (LSM810, Zeiss, Germany), and 6 standardized ROIs per animal were analyzed in a randomized and blinded fashion.
In Vivo Data Analysis and Quantification
Image analysis was performed with Fiji Image J, Version 2.3. Arteries and arterioles were distinguished from veins by autofluorescence of the vessel wall and blood flow direction. Pial vessels were analyzed in axial planes and penetrating arteries were analyzed in coronal or sagittal planes. Microvasospasms were identified by calculating the constriction grade of the spastic vessel compared with a nonspastic vessel segment as previously described.12 Microvasospasm was defined as a reduction of the vessel diameter ≥15% compared with a nonspastic vessel segment.
Statistical Analysis
Data sets were tested for normal distribution with the D’Agostino & Pearson test and presented as ±SEM (±SEM). Otherwise, medians±percentiles were used. Statistically significant differences between groups were tested with Student t tests for parametric data and with the Mann-Whitney U test for nonparametric data using Prism 8 (Graphpad Software LLC).
RESULTS
After SAH induction, brain perfusion was globally reduced in all mice. There was no difference between animals receiving clodronate (Clo) or phosphate-buffered saline (Figure 1C). Sham-operated animals showed no changes in cerebral blood flow.
Number of Brain Macrophages Before and After Depletion
In naive C57BL/6 mice, we found 101±14 CD206+ cells/mm3 without vessel association (meningeal macrophages). Additionally, we also found 671±28 CD206+ cells/mm3 associated with vessels, that is, PVMs. PVMs have an elongated shape and wrap around microvessels (Figure 2A). Most PVMs were located adjacent to pial arteries (276±24/mm3); PVM density on intraparenchymal vessels was somewhat lower (precapillary arteries: 238±16/mm3 and penetrating arteries; 163±15/ mm3; Figure 2B), but still 3 to 5 times higher than the number of meningeal macrophages.
Application of clodronate-loaded liposomes depleted almost all PVMs within 7 days (Figure 3A). Quantification of the immunohistochemical stainings revealed a reduction in the number of PVMs from around 670 PVMs/mm3 in naïve mice, a number well in line with our previous quantification (Figure 2B), to only 46±14 PVMs/mm3 (P<0.001), that is, a reduction of approximately 93%. Interestingly, we also observed a small but significant increase in the number of PVMs in vehicle-treated mice compared with naive animals (Figure 3B; P<0.001), suggesting that an injection with a thin glass capillary through the atlanto-occipital membrane was sufficient to induce PVM proliferation to a small extent. Since the morphology of the PVMs was the same as in unhandled mice (Figure 3A), a major activation of these cells at the time of SAH could be excluded with a sufficiently high degree of confidence.
Number of Brain Macrophages After SAH
Six hours after SAH, brain macrophages remained unchanged regarding morphology or distribution compared with naive mice (Figure 4A); however, their number increased (Figure 4B and 4C). While the number of meningeal CD206+ cells increased without reaching statistical significance (Figure 4B; P=0.07), the number of PVMs more than doubled after SAH (Figure 4C; P<0.001). These findings suggest that PVMs proliferate particularly rapidly when they come into contact with perivascular blood.
Depletion of PVMs Reduces Microvasospasms After SAH
As previously described,7,10,13 SAH induces a high number of microvasospasm (Figure 5A and 5B) in pial and penetrating arterioles (Figure 5C and 5D). In mice depleted of PVMs, the number of microvasospasm was reduced by 66% (Figure 5A and 5B; 9 IQR 5 versus 3 IQR 3) and the proportion of spastic pial and penetrating arterioles was also reduced (Figure 5C and 5D). These findings suggest that PVMs are critically involved in the formation of microvasospasm.
DISCUSSION
SAH leads to microvascular constriction and microvasospasm formation in the subacute and acute phase, which decreases cortical perfusion thereby causing tissue ischemia and subsequent early brain injury.6–8,13 PVMs were shown to improve outcome after SAH9; however, it remains unclear how this protective effect was mediated in regard to microvasospasm formation. In the present study, we reproduced previous results from our laboratory that pial and penetrating arterioles constrict acutely after SAH in vivo7,10,13 performed the first detailed characterizations of the location and morphology of macrophages in relation to the cortical microcirculation and confirmed that intrathecal injection of clodronate-loaded liposomes depleted >90% of PVMs. The main finding of the current study is that depletion of PVMs reduces early microvasospasm formation to a large degree (−70%). These results suggest that PVMs play an important and so far unrecognized role in the formation of microvasospasm after SAH.
Resident brain macrophages originate from yolk sac progenitors, populate the brain in early development, and have been identified to play a critical role in the maintenance of brain homeostasis.14 Depending on their anatomic location, macrophages are categorized as PVM, associated with pial arteries or penetrating arterioles, or meningeal (MM). PVMs have been shown to be a major source of reactive oxygen species, to mediate neurovascular dysfunction,15 and to be involved in the pathophysiology of diverse brain diseases such as Alzheimer disease, multiples sclerosis, CNS infections, and arterial hypertension.14,15 Intrathecal injection of clodronate liposomes, which are taken up by brain macrophages and induce apoptosis, allows to specifically diminish this distinct cell population from the brain and to study their role in various disease models.16
All experiments were performed and analyzed in a fully randomized and blinded manner using a clinically relevant SAH model. Since humans also have PVMs and a very similar microvascular anatomy compared with mice,17 we have sufficient evidence to believe that our results are robust and mirror the events which also occur in the human brain after SAH.
The endovascular filament perforation model employed in our study is the most frequently used preclinical SAH model since it can replicate important pathophysiological features of SAH in a satisfactory manner, for example, vessel rupture and endothelial damage.18 Other mouse models are not able to reproduce these features, which underlines the relevance and great translational potential of the SAH model used in our study, indicating that our results can be considered robust, while minimizing methodological bias.
Despite the apparent involvement of PVMs in microvasospasm formation, the underlying molecular mechanisms need further investigation. The starting point of a cascade of events finally leading to microvasospasm seems to be found in blood degradation products,19 which already have been demonstrated to negatively impact the cerebral microcirculation after SAH.10 Within hours after bleeding onset, erythrocytes are phagocytosed and degraded by macrophages as already shown after intracerebral hemorrhage.20,21 Alternatively, erythrocytes may also decompose by autolysis.22 These processes result in the release of blood degradation products, for example, free iron and hemoglobin, which then accumulate at high concentrations in the narrow perivascular space.19 Free hemoglobin is a very potent nitric oxide (NO) scavenger and may therefore cause local depletion of NO und subsequent vasoconstriction.23 A reason to think that this mechanism occurs after SAH is supported by experiments demonstrating that application of NO to cerebral microvessels resolves microvasospasm and improves outcome after experimental SAH.8,24 Further, hemoglobin degradation products, for example, propentdyopents or bilirubin oxidation end products, may directly induce constriction of cerebral microvessels.25,26 Another possible mechanism by which PVMs could trigger microvasospasm (that may be used for therapeutic purposes) is the activation by blood or blood degradation products and the subsequent release of inflammatory cytokines and free radical species.17 Free radicals are potent NO scavengers and may, in the end, cause local vasoconstriction. The fact that free radicals do not have a long half-live in living tissues and cannot readily pass cell membranes may explain why microvasospasm have a pearl string like morphology, that is, spasms occur only at the site where free radicals are produced by PVMs. Further experiments measuring free radical species in spastic microvessels, however, are needed to clarify this process in the future.
Apart from PVMs, neutrophil-triggered inflammation seems to be a relevant factor in early microvascular changes following SAH.27 In the endovascular filament model, neutrophils have been shown to mediate early cerebral cortical hypoperfusion and oxidative stress after SAH, suggesting that targeting neutrophil function and neutrophil-induced oxidative stress may serve a novel approach to mitigate cerebral hypoperfusion early after SAH.28 Analogous to our results where PVM depletion leads to decreased microvasospasm formation and potentially improves cortical perfusion and tissue ischemia, reduction of neutrophil activity seems to decrease early microvascular injury after SAH and implies that neutrophil-targeted interventions may ameliorate early brain injury or at least limit microvascular injury after SAH.27 Moreover, neutrophil extracellular traps (NETs) that promote neuroinflammation after SAH may be potential therapeutic targets since pharmacological inhibition of NETs demonstrated anti-inflammatory effects by decreasing the levels of proinflammatory factors caused by SAH.29 Similarly, inhibiting NETs may reduce microthrombosis and therefore attenuate early brain injury after SAH.30
Despite its apparent advantages, the current study has also some limitations. Clodronate had to be applied by intrathecal injection; however, the application of vehicle alone already increased the number of CD206+ cells compared with naive mice. Although these cells had the same morphology as perivascular and meningeal macrophages, we cannot completely rule out that these cells were not blood macrophages, which infiltrated the subarachnoid space after injection rather than proliferated PVMs. To take the potential influence by blood borne macrophages on our results into consideration, we always used naive mice as controls for all depletion experiments (where all macrophages were depleted by clodronate treatment).16
Another potential limitation is that we performed in vivo microscopy through a relatively small cranial window, which allowed us to analyze only a certain fraction of the cerebral cortex. Thus, we cannot generalize our findings to the entire brain.
In conclusion, our results suggest that PVMs mediate the formation of microvasospasm early after SAH. We think that the underlying mechanisms are either the release of free radicals by PVMs and subsequent NO scavenging or the degradation of red blood cells by PVMs, which result in increase of perivascular blood degradation and subsequent NO depletion. Since distinguishing between these 2 mechanistic pathways may have therapeutic consequences, further studies are needed to fully understand the molecular mechanisms of microvasospasm formation after SAH.
ARTICLE INFORMATION
Supplemental Material
ARRIVE Checklist
Tables S1–S2
Figures S1–S2
Acknowledgments
We would like to thank Uta Mamrak for excellent technical and organizational support.
Footnote
Nonstandard Abbreviations and Acronyms
- NO
- nitric oxide
- PVM
- perivascular macrophage
- SAH
- subarachnoid hemorrhage
Supplemental Material
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Received: 20 December 2022
Revision received: 8 May 2023
Accepted: 16 May 2023
Published online: 16 June 2023
Published in print: August 2023
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Disclosures None.
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This project was supported by the “Fakultätsförderprogramm für Forschung und Lehre” (FöFoLe; project No. 1075) to Dr Schwarting by the Medical Faculty of the University of Munich and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy – ID 390857198). Dr Lin was funded by the China Scholarship Council (CSC).
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- Emerging Role of Neutrophil Extracellular Traps in Subarachnoid Hemorrhage, Stroke, 55, 12, (2882-2884), (2024).https://doi.org/10.1161/STROKEAHA.124.049321
- Perivascular Neutrophil Extracellular Traps Exacerbate Microvasospasm After Experimental Subarachnoid Hemorrhage, Stroke, 55, 12, (2872-2881), (2024)./doi/10.1161/STROKEAHA.124.047574
- CT perfusion-guided administration of IV milrinone is associated with a reduction in delayed cerebral infarction after subarachnoid hemorrhage, Scientific Reports, 14, 1, (2024).https://doi.org/10.1038/s41598-024-65706-w
- A cell-autonomous role for border-associated macrophages in ApoE4 neurovascular dysfunction and susceptibility to white matter injury, Nature Neuroscience, 27, 11, (2138-2151), (2024).https://doi.org/10.1038/s41593-024-01757-6
- Perivascular macrophages in cerebrovascular diseases, Experimental Neurology, 374, (114680), (2024).https://doi.org/10.1016/j.expneurol.2024.114680
- Single-Cell Transcriptomics Revealed White Matter Repair Following Subarachnoid Hemorrhage, Translational Stroke Research, (2024).https://doi.org/10.1007/s12975-024-01265-6
- All Three Supersystems—Nervous, Vascular, and Immune—Contribute to the Cortical Infarcts After Subarachnoid Hemorrhage, Translational Stroke Research, (2024).https://doi.org/10.1007/s12975-024-01242-z
- Endothelial cells and macrophages as allies in the healthy and diseased brain, Acta Neuropathologica, 147, 1, (2024).https://doi.org/10.1007/s00401-024-02695-0
- Depletion of perivascular macrophages delays ALS disease progression by ameliorating blood-spinal cord barrier impairment in SOD1G93A mice, Frontiers in Cellular Neuroscience, 17, (2023).https://doi.org/10.3389/fncel.2023.1291673
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