Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown

Ogura, Shuntaro; Kurata, Kaori; Hattori, Yukio; Takase, Hiroshi; Ishiguro‐Oonuma, Toshina; Hwang, Yoonha; Ahn, Soyeon; Park, Inwon; Ikeda, Wataru; Kusuhara, Sentaro; Fukushima, Yoko; Nara, Hiromi; Sakai, Hideto; Fujiwara, Takashi; Matsushita, Jun; Ema, Masatsugu; Hirashima, Masanori; Minami, Takashi; Shibuya, Masabumi; Takakura, Nobuyuki; Kim, Pilhan; Miyata, Takaki; Ogura, Yuichiro; Uemura, Akiyoshi

doi:10.1172/jci.insight.90905

Cited by 117 publications

(117 citation statements)

References 61 publications

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“…Similar persistent inflammation in the absence of pericytes as in the brain vasculature in Pdgfb ret/ret mice has been described in the retina 22–25 . Whether an acute drop-out of pericytes in the adult organism leads to altered BBB permeability and alters the permissiveness of vasculature to leukocyte trafficking needs further studies.…”

Section: Discussionsupporting

confidence: 73%

Pericytes regulate vascular immune homeostasis in the CNS

Torok

Schreiner

Tsai

et al. 2019

Preprint

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21Brain endothelium possesses several organ-specific features collectively known as the blood-22 brain barrier (BBB). In addition, trafficking of immune cells in the healthy central nervous 23 system (CNS) is tightly regulated by CNS vasculature. In CNS autoimmune diseases such as 24 multiple sclerosis (MS), these homeostatic mechanisms are overcome by autoreactive 25 2 lymphocyte entry into the CNS causing inflammatory demyelinating immunopathology. 26Previous studies have shown that pericytes regulate the development of organ-specific 27 characteristics of brain vasculature such as the BBB and astrocytic end-feet. Whether pericytes 28 are involved in the control of leukocyte trafficking remains elusive. Using adult, pericyte-29 deficient mice (Pdgfb ret/ret ), we show here that brain vasculature devoid of pericytes shows 30 increased expression of VCAM-1 and ICAM-1, which is accompanied by increased leukocyte 31 infiltration of dendritic cells, monocytes and T cells into the brain, but not spinal cord 32 parenchyma. Regional differences enabling leukocyte trafficking into the brain as opposed to 33 the spinal cord inversely correlate with the pericyte coverage of blood vessels. Upon induction 34 of experimental autoimmune encephalitomyelitis (EAE), pericyte-deficient mice succumb to 35 severe neurological impairment. Treatment with first line MS therapy -fingolimod significantly 36 reverses EAE, indicating that the observed phenotype is due to the massive influx of immune 37 cells into the brain. Furthermore, pericyte-deficiency in mice that express myelin 38 oligodendrocyte glycoprotein peptide (MOG35-55) specific T cell receptor (Pdgfb ret/ret ; 2D2 Tg ) 39 leads to the development of spontaneous neurological symptoms paralleled by massive influx 40 of leukocytes into the brain, suggesting altered brain vascular immune quiescence as a prime 41 cause of exaggerated neuroinflammation. Thus, we show that pericytes indirectly restrict 42 immune cell transmigration into the CNS under homeostatic conditions and during 43 autoimmune-driven neuroinflammation by inducing immune quiescence of brain endothelial 44 cells. 45 46 leukocytes into brain parenchyma, thus contributing to immune privilege of the CNS. BBB 51 function is induced by neural tissue and established by all cell types constituting the 52 neurovascular unit (NVU). Pericytes and mural cells residing on the abluminal side of 53 capillaries and post-capillary venules, regulate several features of the BBB 1, 2 . Studies on Pdgfb 54and Pdgfrb mouse mutants, which exhibit variable pericyte loss, have demonstrated that 55 pericytes negatively regulate endothelial transcytosis which, if not suppressed, leads to 56 increased BBB permeability to plasma proteins 1, 2 . In addition, pericyte-deficient vessels show 57 abnormal astrocyte end-feet polarization 1 . Thus, pericytes regulate several characteristics of 58 brain vasculature during development and in the adult organism 1, 2 . Whether the non-59 permissive properties of brain vasculature to leukocyte traffic...

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Section: Discussionsupporting

confidence: 73%

Pericytes regulate vascular immune homeostasis in the CNS

Torok

Schreiner

Tsai

et al. 2019

Preprint

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“…Our results show that NOTCH2 regulates the expression of PDGFRB on ASC, which is a prime chemotactic receptor of mural cells, that is, pericytes . The retina has a specialized form of the blood brain barrier and the inhibition of PDGFRB signaling in developing murine retinas disrupted transendothelial barriers and caused vascular leakage , very similar to blood‐retina barrier (BRB) changes in DR. This is likely due to the lack of sufficient support by pericytes.…”

Section: Discussionmentioning

confidence: 73%

The Pericytic Phenotype of Adipose Tissue-Derived Stromal Cells Is Promoted by NOTCH2

et al. 2017

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Long-term diabetes leads to macrovascular and microvascular complication. In diabetic retinopathy (DR), persistent hyperglycemia causes permanent loss of retinal pericytes and aberrant proliferation of microvascular endothelial cells (ECs). Adipose tissue-derived stromal cells (ASCs) may serve to functionally replace retinal pericytes and normalize retinal microvasculature during disease progression. We hypothesized that Notch signaling in ASC underlies regulation and stabilization of dysfunctional retinal microvascular networks such as in DR. ASC prominently and constitutively expressed NOTCH2. Genetic knockdown of NOTCH2 in ASC (SH-NOTCH2) disturbed the formation of vascular networks of human umbilical cord vein endothelial cells both on monolayers of ASC and in organotypical three-dimensional cocultures with ASC. On ASC SH-NOTCH2, cell surface platelet-derived growth factor receptor beta was downregulated which disrupted their migration toward the chemoattractant platelet-derived growth factor beta subunits (PDGF-BB) as well as to conditioned media from EC and bovine retinal EC. This chemoattractant is secreted by pro-angiogenic EC in newly formed microvascular networks to attract pericytes. Intravitreal injected ASC SH-NOTCH2 in oxygen-induced retinopathy mouse eyes did not engraft in the preexisting retinal microvasculature. However, the in vivo pro-angiogenic capacity of ASC SH-NOTCH2 did not differ from controls. In this respect, multifocal electroretinography displayed similar b-wave amplitudes in the avascular zones when either wild type ASC or SH-NOTCH2 ASC were injected. In conclusion, our results indicate that NOTCH2 is essential to support in vitro vasculogenesis via juxtacrine interactions. In contrast, ongoing in vivo angiogenesis is influenced by paracrine signaling of ASC, irrespective of Notch signaling. STEM CELLS 2018;36:240-251 SIGNIFICANCE STATEMENTIn this study, NOTCH2 is identified as a novel regulator of pericytic phenotype of human adipose tissue-derived stromal cells (ASCs). Results show that NOTCH2 modulates (a) ASC migration to the retinal microenvironment and (b) endothelial cells assembly in a vessel network formation in vitro. At the molecular level, NOTCH2 promotes the ASC pericytic phenotype through plateletderived growth factor receptor beta expression and sensitivity to chemoattractant.

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“…In the early stages of diabetic retinopathy, hyperglycaemia and chronic inflammation damage the retinal endothelium and play a key role in further vascular leakage, pericyte loss, increased acellular vessels and the eventual manifestation of clinical diabetic retinopathy symptoms [40,41]. Leucostasis is a characteristic of diabetic retinopathy inflammation [25,42].…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

Wang

Xie

et al. 2018

Diabetologia

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Aims/hypothesis Diabetic retinopathy is a common microvascular complication of diabetes mellitus and is initiated by inflammation and apoptosis-associated retinal endothelial cell damage. Prostaglandin E 2 (PGE 2 ) has emerged as a critical regulator of these biological processes. We hypothesised that modulating PGE 2 and its E-prostanoid receptor (EP 2 R) would prevent diabetes mellitus-induced inflammation and microvascular dysfunction. Methods In a streptozotocin (STZ)-induced rat model of diabetes, rats received intravitreal injection of PGE 2 , butaprost (a PGE 2 / EP 2 R agonist) or AH6809 (an EP 2 R antagonist). Retinal histology, optical coherence tomography, ultrastructure of the retinal vascular and biochemical markers were assessed. Results Intravitreal injection of PGE 2 and butaprost significantly accelerated retinal vascular leakage, leucostasis and endothelial cell apoptosis in STZ-induced diabetic rats. This response was ameliorated in diabetic rats pre-treated with AH6809. In addition, pre-treatment of human retinal microvascular endothelial cells with AH6809 attenuated PGE 2 -and butaprost-induced activation of caspase 1, activation of the complex containing nucleotide-binding domain and leucine rich repeat containing family, pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a C-terminal caspase-activation and recruitment domain (ASC), and activation of the EP 2 R-coupled cAMP/protein kinase A/cAMP response element-binding protein signalling pathway. Conclusions/interpretation The PGE 2 /EP 2 R signalling pathway is involved in STZ-induced diabetic retinopathy and could be considered as a potential target for diabetic retinopathy prevention and treatment.

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Sustained inflammation after pericyte depletion induces irreversible blood-retina barrier breakdown

Cited by 117 publications

References 61 publications

Pericytes regulate vascular immune homeostasis in the CNS

Pericytes regulate vascular immune homeostasis in the CNS

The Pericytic Phenotype of Adipose Tissue-Derived Stromal Cells Is Promoted by NOTCH2

Prostaglandin E2/EP2 receptor signalling pathway promotes diabetic retinopathy in a rat model of diabetes

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