Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice

Nguyen, Quang Linh; Okuno, Noriko; Hamashima, Takeru; Dang, Son Tung; Fujikawa, Miwa; Ikoma, Yoko; Enomoto, Atsushi; Maki, Takakuni; Nguyen, Hoang; Nguyen, Van Tuyen; Fujimori, Toshihiko; Mori, Hisashi; Andræ, Johanna; Betsholtz, Christer; Takao, Keizo; Yamamoto, Seiji; Sasahara, Masakiyo

doi:10.1007/s10456-020-09742-w

Cited by 35 publications

(21 citation statements)

References 43 publications

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“…PDGFRA encodes a cell surface tyrosine kinase receptor for members of PDGF family. These growth factors are mitogens for cells, which plays a role in organ development, wound healing, and tumor progression 33 . PKCη is a member of the novel PKC isozymes that regulates cell proliferation, differentiation, secretion and apoptosis 34 , 35 .…”

Section: Discussionmentioning

confidence: 99%

METTL3-mediated N⁶-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication

Suo¹,

Liu²,

Zhang³

et al. 2022

Theranostics

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Rationale: Microvascular complication is a major cause of morbidity and mortality among the patients with diabetes. Pericyte dysfunction is the predominant pathological manifestation of microvascular complication. N 6 -methyladenosine (m 6 A) serves as the most prevalent modification in eukaryotic mRNAs. However, the role of m 6 A RNA modification in pericyte dysfunction is still unclear. Methods: Quantitative polymerase chain reactions and western blots were conducted to detect the change of m 6 A RNA modification in pericytes and mouse retinas following diabetic stress. MTT assay, transwell migration assay, caspase 3/7 activity assay, calcein-AM/propidium iodide (PI) staining, and TUNEL staining were conducted to determine the role of METTL3 in pericyte biology in vitro . Retinal trypsin digestion, vascular permeability assay, and IB4-NG2 double immunofluorescent staining were conducted to determine the role of METTL3 in retinal pericyte dysfunction and vascular complication. RNA sequencing, RNA pull-down assays and immunoblots were conducted to clarify the mechanism of METTL3-mediated pericyte dysfunction and vascular complication. Results: The levels of m 6 A RNA methylation were significantly up-regulated in pericytes and mouse retinas following diabetic stress, which were caused by increased expression of METTL3. METTL3 regulated the viability, proliferation, and differentiation of pericytes in vitro . Specific depletion of METTL3 in pericytes suppressed diabetes-induced pericyte dysfunction and vascular complication in vivo . METTL3 overexpression impaired pericyte function by repressing PKC-η, FAT4, and PDGFRA expression, which was mediated by YTHDF2-dependent mRNA decay. Conclusion: METTL3-mediated m 6 A methylation epigenetically regulates diabetes-induced pericyte dysfunction. METTL3-YTHDF2-PKC-η/FAT4/PDGFRA signaling axis could be therapeutically targeted for treating microvascular complications.

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Section: Discussionmentioning

confidence: 99%

METTL3-mediated N⁶-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication

Suo¹,

Liu²,

Zhang³

et al. 2022

Theranostics

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“…In this process, pericytes attach to the ECs, regulate the formation of the extracellular matrix and tight junctions between endothelial cells, and maintain the integrity of immature blood vessels ( Franco et al, 2011 ). Pericytes interact with ECs through a variety of signaling pathways to regulate angiogenesis, including the PDGF-B/PDGFR-B, angiopoietin (Ang)/Tie2, VEGF/VEGFR, Notch1, and Notch 3 signaling pathways ( Berger et al, 2005 ; Nakamura et al, 2016 ; Leligdowicz et al, 2018 ; Özen et al, 2018 ; Shibahara et al, 2020a ; Gong et al, 2021 ; Nguyen et al, 2021 ), and these pathways are summarized in Figure 2 . Finally, the tip cells anastomose with adjacent vascular buds to form a microvascular ring.…”

Section: The Role Of Pericytes In Ischemic Strokementioning

confidence: 99%

“…IS is accompanied by a series of molecular and cellular events, which include immune inflammatory response, glial cell activation, blood–brain barrier (BBB) destruction, and neuronal cell death. Previous treatments for IS focused on vascular recanalization and neuroprotection ( Molina and Saver, 2005 ; Nguyen et al, 2021 ); however, recent studies have shown that the outcome of these treatments may be affected by the components of the neurovascular unit (NVU) ( ElAli et al, 2014 ; Morrison and Filosa, 2019 ; Cao et al, 2021 ; Le Roy et al, 2021 ; Wang L. et al, 2021 ). Therefore, targeting the NVU is being approached as a new treatment strategy for IS.…”

Section: Introductionmentioning

confidence: 99%

The Role of Pericytes in Ischemic Stroke: Fom Cellular Functions to Therapeutic Targets

Zhou

Guo

Zhang

et al. 2022

Front. Mol. Neurosci.

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Ischemic stroke (IS) is a cerebrovascular disease causing high rates of disability and fatality. In recent years, the concept of the neurovascular unit (NVU) has been accepted by an increasing number of researchers and is expected to become a new paradigm for exploring the pathogenesis and treatment of IS. NVUs are composed of neurons, endothelial cells, pericytes, astrocytes, microglia, and the extracellular matrix. As an important part of the NVU, pericytes provide support for other cellular components and perform a variety of functions, including participating in the maintenance of the normal physiological function of the blood–brain barrier, regulating blood flow, and playing a role in inflammation, angiogenesis, and neurogenesis. Therefore, treatment strategies targeting pericyte functions, regulating pericyte epigenetics, and transplanting pericytes warrant exploration. In this review, we describe the reactions of pericytes after IS, summarize the potential therapeutic targets and strategies targeting pericytes for IS, and provide new treatment ideas for ischemic stroke.

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“…Next, fluorescence quantitative PCR was conducted using the SYBR® Premix ExTaq™ II kit (RR820A, Takara) on an ABI 7500 quantitative PCR instrument (7500, ABI Company, Oyster Bay, N.Y., USA). All samples were normalized to U6 and GAPDH using the 2 -ΔΔCT method [51].…”

Section: Reverse Transcription-quantitative Polymerase Chainmentioning

confidence: 99%

Bevacizumab‐Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

Tian

Yue

et al. 2021

Oxidative Medicine and Cellular Longevity

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The molecular mechanisms underlying the cardiotoxicity associated with bevacizumab, a first-line immunotherapeutic agent used to treat lung cancer, are not fully understood. Here, we examined intracellular signal transduction in cardiomyocytes after exposure to different doses of bevacizumab in vitro. Our results demonstrated that bevacizumab significantly and dose-dependently reduces cardiomyocyte viability and increases cell apoptosis. Bevacizumab treatment also led to mitochondrial dysfunction in cardiomyocytes, as evidenced by the decreased ATP production, increased ROS production, attenuated antioxidative enzyme levels, and reduced respiratory complex function. In addition, bevacizumab induced intracellular calcium overload, ER stress, and caspase-12 activation. Finally, bevacizumab treatment inhibited the ERK signaling pathway, which, in turn, significantly reduced cardiomyocyte viability and contributed to mitochondrial dysfunction. Together, our results demonstrate that bevacizumab-mediated cardiotoxicity is associated with mitochondrial dysfunction, ER stress, and ERK pathway inactivation. These findings may provide potential treatment targets to attenuate myocardial injury during lung cancer immunotherapy.

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Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice

Cited by 35 publications

References 43 publications

METTL3-mediated N⁶-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication

METTL3-mediated N⁶-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication

The Role of Pericytes in Ischemic Stroke: Fom Cellular Functions to Therapeutic Targets

Bevacizumab‐Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

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Vascular PDGFR-alpha protects against BBB dysfunction after stroke in mice

Cited by 35 publications

References 43 publications

METTL3-mediated N6-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication

METTL3-mediated N6-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication

The Role of Pericytes in Ischemic Stroke: Fom Cellular Functions to Therapeutic Targets

Bevacizumab‐Induced Mitochondrial Dysfunction, Endoplasmic Reticulum Stress, and ERK Inactivation Contribute to Cardiotoxicity

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METTL3-mediated N⁶-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication

METTL3-mediated N⁶-methyladenosine modification governs pericyte dysfunction during diabetes-induced retinal vascular complication