Central nervous system pericytes in health and disease

Winkler, Ethan A.; Bell, Robert D.; Zloković, Berislav V.

doi:10.1038/nn.2946

Cited by 838 publications

(897 citation statements)

References 101 publications

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“…In the current study, Pdgfrb expression was also upregulated by chronic hypoperfusion in the BCAS mice. Given that the PDGFRB is important for proliferation and migration of pericytes 55, PDGFRB may be increased in pericytes at a certain point, as compensation for hypoperfusion.…”

Section: Discussionmentioning

confidence: 99%

“…This meant that we could not directly relate our pathological findings to antemortem hypoperfusive and cognitive status. In addition, the lack of comparison of the SVD cases with controls without neurodegenerative pathologies was another limitation considering that PDGFRB positive pericytes may also degenerate in some neurodegenerative diseases 46, 55, 56, 59. The third limitation is that a histopathological study using postmortem human brains does not always uncover the entire cell process that occurs in the ageing human brain.…”

Section: Discussionmentioning

confidence: 99%

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Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

et al. 2017

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Subcortical small vessel disease (SVD) is characterized by white matter damage resulting from arteriolosclerosis and chronic hypoperfusion. Transforming growth factor beta 1 (TGFB1) is dysregulated in the hereditary SVD, CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). However, very little is known about the role of the largest group in the TGFB superfamily – the bone morphogenetic proteins (BMPs) – in SVD pathogenesis. The aim of this study was to characterize signaling abnormalities of BMPs in sporadic SVD. We examined immunostaining of TGFB1 and BMPs (BMP2/BMP4/BMP6/BMP7/BMP9) in a total of 19 post‐mortem human brain samples as follows: 7 SVD patients (4 males, 76–90 years old); 6 Alzheimer's disease (AD) patients (2 males, 67–93 years old) and 6 age‐matched disease controls (3 males, 68–78 years old). We subsequently investigated the effects of oxygen–glucose deprivation and BMP4 addition on cultured cells. Furthermore, adult mice were subjected to chronic cerebral hypoperfusion using bilateral common carotid artery stenosis, followed by continuous intracerebroventricular infusion of the BMP antagonist, noggin. In the SVD cases, BMP4 was highly expressed in white matter pericytes. Oxygen–glucose deprivation induced BMP4 expression in cultured pericytes in vitro. Recombinant BMP4 increased the number of cultured endothelial cells and pericytes and converted oligodendrocyte precursor cells into astrocytes. Chronic cerebral hypoperfusion in vivo also upregulated BMP4 with concomitant white matter astrogliogenesis and reduced oligodendrocyte lineage cells, both of which were suppressed by intracerebroventricular noggin infusion. Our findings suggest ischemic white matter damage evolves in parallel with BMP4 upregulation in pericytes. BMP4 promotes angiogenesis, but induces astrogliogenesis at the expense of oligodendrocyte precursor cell proliferation and maturation, thereby aggravating white matter damage. This may explain white matter vulnerability to chronic hypoperfusion. The regulation of BMP4 signaling is a potential therapeutic strategy for treating SVD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

et al. 2017

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“…9,25 Future longitudinal CSF and BBB imaging biomarkers studies in living human APOE4 and APOE3 carriers with no cognitive impairment and/or with mild cognitive impairment should continue interrogating the role of BBB breakdown in the pathogenesis of dementia because of AD and other causes, as well as the role of pericyte loss and the studied molecular biomarkers of BBB breakdown in the living human brain.…”

mentioning

confidence: 99%

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

Halliday

Rege

et al. 2015

J Cereb Blood Flow Metab

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519

478

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The blood-brain barrier (BBB) limits the entry of neurotoxic blood-derived products and cells into the brain that is required for normal neuronal functioning and information processing. Pericytes maintain the integrity of the BBB and degenerate in Alzheimer's disease (AD). The BBB is damaged in AD, particularly in individuals carrying apolipoprotein E4 (APOE4) gene, which is a major genetic risk factor for late-onset AD. The mechanisms underlying the BBB breakdown in AD remain, however, elusive. Here, we show accelerated pericyte degeneration in AD APOE4 carriers >AD APOE3 carriers >non-AD controls, which correlates with the magnitude of BBB breakdown to immunoglobulin G and fibrin. We also show accumulation of the proinflammatory cytokine cyclophilin A (CypA) and matrix metalloproteinase-9 (MMP-9) in pericytes and endothelial cells in AD (APOE4 >APOE3), previously shown to lead to BBB breakdown in transgenic APOE4 mice. The levels of the apoE lipoprotein receptor, low-density lipoprotein receptor-related protein-1 (LRP1), were similarly reduced in AD APOE4 and APOE3 carriers. Our data suggest that APOE4 leads to accelerated pericyte loss and enhanced activation of LRP1-dependent CypA-MMP-9 BBB-degrading pathway in pericytes and endothelial cells, which can mediate a greater BBB damage in AD APOE4 compared with AD APOE3 carriers.

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“…The present pharmacological experiment using the selective PDGFR inhibitor STI571 largely diminished proliferation of endothelial cells in the NH of adult mice. The signaling of PDGFB and PDGFRB plays a crucial role in the interaction of pericytes with endothelial cells by controlling the migration and shape conversion of pericytes (Lindahl et al 1997, Fukushi et al 2004, Ribatti et al 2011, Winkler et al 2011. The PDGFR inhibitor STI571 has been shown to inhibit angiogenesis by preventing PDGFRB of pericytes (Bauman et al 2007, Rocha et al 2007.…”

Section: Significance Of Vegf Signalingmentioning

confidence: 99%

“…The deficiency of Vegfa or Vegfr2 genes appears to be lethal due to abnormal blood vessel development (Shalaby et al 1995, Carmeliet et al 1996. The signaling pathway of platelet-derived growth factor B (PDGFB) and PDGF receptor beta (PDGFRB) is responsible for the recruitment of pericytes to new-born endothelial cells and controls the migration and shape conversion of pericytes (Lindahl et al 1997, Fukushi et al 2004, Winkler et al 2011. It has been shown that the embryos of Pdgfb-or Pdgfrb-deficient mice continue to develop until embryonic days 16-19, but widespread hemorrhage and edema cause embryonic lethality before birth (Lindahl et al 1997).…”

Section: Introductionmentioning

confidence: 99%

VEGF-dependent and PDGF-dependent dynamic neurovascular reconstruction in the neurohypophysis of adult mice

Furube¹,

Mannari²,

Morita³

et al. 2014

Journal of Endocrinology

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Hypothalamo-neurohypophysial system (HNS) releases arginine vasopressin (AVP) and oxytocin (OXT) from axonal terminals of the neurohypophysis (NH) into blood circulation for controlling body fluid homeostasis and lactation. Chronic osmotic and suckling stimulations have been shown to cause neurovascular and neuroglial reconstruction in the NH of adult mammals and no study has been reported for vascular dynamics. The aim of this study was to elucidate the occurrence of continuous angiogenesis and growth factor-dependent neurovascular reconstruction in the NH of adult mice. Active proliferation of endothelial cells and oligodendrocyte progenitor cells (OPCs) was observed using the immunohistochemistry of bromodeoxyuridine and Ki-67. Vascular endothelial growth factor A (VEGFA) and VEGF receptor 2 (VEGFR2 (KDR)) were highly expressed at pituicytes and endothelial cells respectively. Moreover, prominent expression of platelet-derived growth factor B (PDGFB) and PDGF receptor beta was observed at OXT-containing axonal terminals and pericytes respectively. Administration of the selective tyrosine kinase inhibitor AZD2171 for VEGFRs and STI571 for PDGFRs significantly decreased proliferation of endothelial cells and OPCs. Moreover, AZD2171 treatment decreased vascular density by facilitating apoptosis of endothelial cells and the withdrawal of its treatment led to remarkable rebound proliferation of endothelial cells, so that vascular density rapidly returned to normal levels. AZD2171 decreased the density of both AVP-and OXT-containing axonal terminals, whereas STI571 selectively decreased the density of AVP-containing ones. Thus, this study demonstrates that the signaling pathways of VEGF and PDGF are crucial mediators for determining proliferation of endothelial cells and OPCs and the density of AVP-and OXT-containing axonal terminals in the HNS.

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Central nervous system pericytes in health and disease

Cited by 838 publications

References 101 publications

Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

Pericyte‐derived bone morphogenetic protein 4 underlies white matter damage after chronic hypoperfusion

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

VEGF-dependent and PDGF-dependent dynamic neurovascular reconstruction in the neurohypophysis of adult mice

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