Reductions in brain pericytes are associated with arteriovenous malformation vascular instability

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Brain arteriovenous malformations (bAVMs) are rupture-prone tangles of blood vessels with direct shunting of blood flow between arterial and venous circulations. The molecular and/or cellular mechanisms contributing to bAVM pathogenesis and/or destabilization in sporadic lesions have remained elusive. Initial insights into AVM formation have been gained through models of genetic AVM syndromes. And while many studies have focused on endothelial cells, the contributions of other vascular cell types have yet to be systematically studied. Pericytes are multifunctional mural cells that regulate brain angiogenesis, blood-brain barrier integrity, and vascular stability. Here, the authors analyze the abundance of brain pericytes and their association with vascular changes in sporadic human AVMs.


Tissues from bAVMs and from temporal lobe specimens from patients with medically intractable epilepsy (nonvascular lesion controls [NVLCs]) were resected. Immunofluorescent staining with confocal microscopy was performed to quantify pericytes (platelet-derived growth factor receptor–beta [PDGFRβ] and aminopeptidase N [CD13]) and extravascular hemoglobin. Iron-positive hemosiderin deposits were quantified with Prussian blue staining. Syngo iFlow post–image processing was used to measure nidal blood flow on preintervention angiograms.


Quantitative immunofluorescent analysis demonstrated a 68% reduction in the vascular pericyte number in bAVMs compared with the number in NVLCs (p < 0.01). Additional analysis demonstrated 52% and 50% reductions in the vascular surface area covered by CD13- and PDGFRβ-positive pericyte cell processes, respectively, in bAVMs (p < 0.01). Reductions in pericyte coverage were statistically significantly greater in bAVMs with prior rupture (p < 0.05). Unruptured bAVMs had increased microhemorrhage, as evidenced by a 15.5-fold increase in extravascular hemoglobin compared with levels in NVLCs (p < 0.01). Within unruptured bAVM specimens, extravascular hemoglobin correlated negatively with pericyte coverage (CD13: r = −0.93, p < 0.01; PDGFRβ: r = −0.87, p < 0.01). A similar negative correlation was observed with pericyte coverage and Prussian blue–positive hemosiderin deposits (CD13: r = −0.90, p < 0.01; PDGFRβ: r = −0.86, p < 0.01). Pericyte coverage positively correlated with the mean transit time of blood flow or the time that circulating blood spends within the bAVM nidus (CD13: r = 0.60, p < 0.05; PDGFRβ: r = 0.63, p < 0.05). A greater reduction in pericyte coverage is therefore associated with a reduced mean transit time or faster rate of blood flow through the bAVM nidus. No correlations were observed with time to peak flow within feeding arteries or draining veins.


Brain pericyte number and coverage are reduced in sporadic bAVMs and are lowest in cases with prior rupture. In unruptured bAVMs, pericyte reductions correlate with the severity of microhemorrhage. A loss of pericytes also correlates with a faster rate of blood flow through the bAVM nidus. This suggests that pericytes are associated with and may contribute to vascular fragility and hemodynamic changes in bAVMs. Future studies in animal models are needed to better characterize the role of pericytes in AVM pathogenesis.

ABBREVIATIONS bAVM = brain arteriovenous malformation; BBB = blood-brain barrier; CD13 = aminopeptidase N; CD31 = platelet endothelial adhesion molecule 1; GFAP = glial fibrillary acidic protein; MTT = mean transit time; NVLC = nonvascular lesion control; PDGFRβ = platelet-derived growth factor receptor–beta; ROI = region of interest.

Article Information

Correspondence Michael T. Lawton: Barrow Neurological Institute, Phoenix, AZ.

INCLUDE WHEN CITING Published online January 5, 2018; DOI: 10.3171/2017.6.JNS17860.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.



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    Cytoarchitecture of the cerebrovasculature in the human cortex. Representative low-magnification confocal microscopy image depicting the close structural relationship among pericytes (PDGFRβ, green), endothelial cells (CD31, red), and astrocytes (GFAP, blue) in human cortex. Inset features a higher-magnification view demonstrating a pericyte cell body (arrowhead) and contiguous stellate process, which ensheathe the endothelial wall.

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    Vascular pericytes are reduced in human bAVMs. Representative confocal microscopy analysis (A) of CD13-positive pericytes (green) and CD31-positive endothelium (red) in human AVMs and temporal cortex from NVLCs. Graphs showing quantification of CD13-positive (B) and PDGFRβ-positive (C) pericyte cells per square millimeter vascular surface area in NVLCs and bAVMs. Graphs showing quantification of pericyte coverage of the vascular wall utilizing CD13 (D) and PDGFRβ (E) immunolabeling of pericyte cell processes. Values in the graphs are expressed as the mean ± standard error of the mean.

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    Reductions in vascular pericytes are associated with acute cerebral microhemorrhage in unruptured bAVMs. A: Representative confocal microscopy analysis of hemoglobin (red) and lectin-positive endothelium in temporal cortex from NVLCs and bAVMs. Yellow indicates colocalized intravascular hemoglobin. B: Graph demonstrating quantification of extravascular hemoglobin immunofluorescent signal from NVLCs (blue) and unruptured bAVMs (red). Values are expressed as the mean ± standard error of the mean. C and D: Graphic representation of correlation between CD13- or PDGFRβ-positive pericyte coverage and extravascular hemoglobin in unruptured bAVM tissue specimens.

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    Pericyte reductions are associated and negatively correlated with chronic microhemorrhage in unruptured bAVMs. A: Representative bright-field microscopy analysis of Prussian blue–positive hemosiderin deposits (blue) with Nuclear fast red counterstain (pink) in bAVMs and temporal cortex from NVLCs. B: Graph demonstrating quantification of Prussian blue–positive hemosiderin deposits from NVLCs (blue) and unruptured bAVMs (red). Values are expressed as the mean ± standard error of the mean. C and D: Graphic representations of correlation between CD13- or PDGFRβ-positive pericyte coverage and hemosiderin deposition in unruptured bAVM tissue specimens.

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    Pericyte reductions positively correlate with blood flow through the bAVM nidus. Representative preoperative angiograms, anteroposterior (A) and lateral (B) views of left internal carotid artery injection, demonstrating Spetzler-Martin grade II, supplementary grade 4 right lateral temporal bAVM. Representative syngo iFlow postprocessing of preintervention angiogram to determine mean iFlow transit time of bAVM nidus, anteroposterior (C) and lateral (D) views of left internal carotid artery injection. Graphic representations of correlation between CD13-positive (E) or PDGFRβ-positive (F) pericyte coverage and MTT of blood flow through the bAVM nidus using iFlow analysis. Each point depicts an individual subject.



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