Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke.

Abstract:

:Intracerebral hemorrhagic stroke and vascular dementia are age- and hypertension-associated manifestations of human cerebral small vessel disease (SVD). Cerebral microvessels are formed by endothelial cells (ECs), which are connected through tight junctions, adherens junctions, and stabilizing basement membrane structures. These endothelial connections ensure both vessel stability and blood-brain barrier (BBB) functions, the latter enabling selective exchange of ions, bioactive molecules, and cells between the bloodstream and brain tissue. Srf(iECKO) mice, permitting conditional EC-specific depletion of the transcription factor Serum Response Factor (SRF), suffer from loss of BBB integrity and intracerebral hemorrhaging. Cerebral microbleeds and larger hemorrhages developed upon postnatal and adult depletion of either SRF or its cofactors Myocardin Related Transcription Factor (MRTF-A/-B), revealing essential requirements of ongoing SRF/MRTF activity for maintenance of cerebral small vessel integrity. In vivo magnetic resonance imaging allowed detection, localization, and time-resolved quantification of BBB permeability and hemorrhage formation in Srf(iECKO) brains. At the molecular level, direct and indirect SRF/MRTF target genes, encoding structural components of tight junctions (Claudins and ZO proteins), adherens junctions (VE-cadherin, α-Actinin), and the basement membrane (Collagen IV), were down-regulated upon SRF depletion. These results identify SRF and its MRTF cofactors as major transcriptional regulators of EC junctional stability, guaranteeing physiological functions of the cerebral microvasculature. We hypothesize that impairments in SRF/MRTF activity contribute to human SVD pathology.

authors

Weinl C,Castaneda Vega S,Riehle H,Stritt C,Calaminus C,Wolburg H,Mauel S,Breithaupt A,Gruber AD,Wasylyk B,Olson EN,Adams RH,Pichler BJ,Nordheim A

doi

10.1073/pnas.1509047112

subject

Has Abstract

pub_date

2015-08-11 00:00:00

pages

9914-9

issue

32

eissn

0027-8424

issn

1091-6490

pii

1509047112

journal_volume

112

pub_type

杂志文章
  • ZNF263 is a transcriptional regulator of heparin and heparan sulfate biosynthesis.

    abstract::Heparin is the most widely prescribed biopharmaceutical in production globally. Its potent anticoagulant activity and safety makes it the drug of choice for preventing deep vein thrombosis and pulmonary embolism. In 2008, adulterated material was introduced into the heparin supply chain, resulting in several hundred d...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1920880117

    authors: Weiss RJ,Spahn PN,Toledo AG,Chiang AWT,Kellman BP,Li J,Benner C,Glass CK,Gordts PLSM,Lewis NE,Esko JD

    更新日期:2020-04-28 00:00:00

  • Risperidone and ritanserin but not haloperidol block effect of dizocilpine on the active allothetic place avoidance task.

    abstract::Spatial working memory or short-term place memory is impaired in schizophrenia. The efficiency of antipsychotic drugs, particularly of typical antipsychotics, on cognitive deficit in schizophrenia remains disputable. Inhibition of serotonin (5-HT) 2A/2C receptors is important for cognitive improvement in schizophrenic...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0711273105

    authors: Bubenikova-Valesova V,Stuchlik A,Svoboda J,Bures J,Vales K

    更新日期:2008-01-22 00:00:00

  • Assembly of cyclin D-dependent kinase and titration of p27Kip1 regulated by mitogen-activated protein kinase kinase (MEK1).

    abstract::A constitutively active form of mitogen-activated protein kinase kinase (MEK1) was synthesized under control of a zinc-inducible promoter in NIH 3T3 fibroblasts. Zinc treatment of serum-starved cells activated extracellular signal-regulated protein kinases (ERKs) and induced expression of cyclin D1. Newly synthesized ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.95.3.1091

    authors: Cheng M,Sexl V,Sherr CJ,Roussel MF

    更新日期:1998-02-03 00:00:00

  • Distinct neural signatures of threat learning in adolescents and adults.

    abstract::Most teenage fears subside with age, a change that may reflect brain maturation in the service of refined fear learning. Whereas adults clearly demarcate safe situations from real dangers, attenuating fear to the former but not the latter, adolescents' immaturity in prefrontal cortex function may limit their ability t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1005494108

    authors: Lau JY,Britton JC,Nelson EE,Angold A,Ernst M,Goldwin M,Grillon C,Leibenluft E,Lissek S,Norcross M,Shiffrin N,Pine DS

    更新日期:2011-03-15 00:00:00

  • Cdc20 associates with the kinase aurora2/Aik.

    abstract::Cdc20/fizzy family proteins are involved in activation of the anaphase-promoting complex/cyclosome, which catalyzes the ubiquitin-dependent proteolysis of cell cycle regulatory proteins such as anaphase inhibitors and mitotic cyclins, leading to chromosome segregation and exit from mitosis. Previous work has shown tha...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.96.13.7306

    authors: Farruggio DC,Townsley FM,Ruderman JV

    更新日期:1999-06-22 00:00:00

  • Replication of acetylaminofluorene-adducted plasmids in human cells: spectrum of base substitutions and evidence of excision repair.

    abstract::In rats fed the liver carcinogen 2-acetylaminofluorene (AAF), the two most abundant types of DNA adduct are N-(deoxyguanosin-8-yl)-2-acetylaminofluorene and its deacetylated derivative. When plasmids carrying AAF adducts replicate in bacteria, the predominant mutations are frameshifts, whereas with deacetylated (AF) a...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.88.22.10193

    authors: Mah MC,Boldt J,Culp SJ,Maher VM,McCormick JJ

    更新日期:1991-11-15 00:00:00

  • Flexible neural mechanisms of cognitive control within human prefrontal cortex.

    abstract::A major challenge in research on executive control is to reveal its functional decomposition into underlying neural mechanisms. A typical assumption is that this decomposition occurs solely through anatomically based dissociations. Here we tested an alternative hypothesis that different cognitive control processes may...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0808187106

    authors: Braver TS,Paxton JL,Locke HS,Barch DM

    更新日期:2009-05-05 00:00:00

  • Purified membrane and soluble folate binding proteins from cultured KB cells have similar amino acid compositions and molecular weights but differ in fatty acid acylation.

    abstract::A membrane-associated folate binding protein (FBP) and a soluble FBP, which is released into the culture medium, have been purified from human KB cells using affinity chromatography. By NaDodSO4/PAGE, both proteins have an apparent Mr of approximately 42,000. However, in the presence of Triton X-100, the soluble FBP e...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.84.18.6546

    authors: Luhrs CA,Pitiranggon P,da Costa M,Rothenberg SP,Slomiany BL,Brink L,Tous GI,Stein S

    更新日期:1987-09-01 00:00:00

  • Extent of N-terminal methionine excision from Escherichia coli proteins is governed by the side-chain length of the penultimate amino acid.

    abstract::In a significant fraction of the Escherichia coli cytosolic proteins, the N-terminal methionine residue incorporated during the translation initiation step is excised. The N-terminal methionine excision is catalyzed by methionyl-aminopeptidase (MAP). Previous studies have suggested that the action of this enzyme could...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.21.8247

    authors: Hirel PH,Schmitter MJ,Dessen P,Fayat G,Blanquet S

    更新日期:1989-11-01 00:00:00

  • Longevity and transposon defense, the case of termite reproductives.

    abstract::Social insects are promising new models in aging research. Within single colonies, longevity differences of several magnitudes exist that can be found elsewhere only between different species. Reproducing queens (and, in termites, also kings) can live for several decades, whereas sterile workers often have a lifespan ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1804046115

    authors: Elsner D,Meusemann K,Korb J

    更新日期:2018-05-22 00:00:00

  • Epstein-Barr virus co-opts TFIIH component XPB to specifically activate essential viral lytic promoters.

    abstract::Epstein-Barr virus (EBV) is associated with epithelial and lymphoid malignancies, establishes latent infection in memory B cells, and intermittently produces infectious virions through lytic replication. Released virions play a key role in latent reservoir maintenance and transmission. Lytic EBV transcription differs ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2000625117

    authors: Verma D,Church TM,Swaminathan S

    更新日期:2020-06-09 00:00:00

  • Induced nucleotide specificity in a GTPase.

    abstract::In signal-recognition particle (SRP)-dependent protein targeting to the bacterial plasma membrane, two GTPases, Ffh (a subunit of the bacterial SRP) and FtsY (the bacterial SRP receptor), act as GTPase activating proteins for one another. The molecular mechanism of this reciprocal GTPase activation is poorly understoo...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0737693100

    authors: Shan SO,Walter P

    更新日期:2003-04-15 00:00:00

  • Monomeric G protein-coupled receptor rhodopsin in solution activates its G protein transducin at the diffusion limit.

    abstract::G protein-coupled receptors mediate biological signals by stimulating nucleotide exchange in heterotrimeric G proteins (Galphabetagamma). Receptor dimers have been proposed as the functional unit responsible for catalytic interaction with Galphabetagamma. To investigate whether a G protein-coupled receptor monomer can...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0701967104

    authors: Ernst OP,Gramse V,Kolbe M,Hofmann KP,Heck M

    更新日期:2007-06-26 00:00:00

  • Detailing the optimality of photosynthesis in cyanobacteria through systems biology analysis.

    abstract::Photosynthesis has recently gained considerable attention for its potential role in the development of renewable energy sources. Optimizing photosynthetic organisms for biomass or biofuel production will therefore require a systems understanding of photosynthetic processes. We reconstructed a high-quality genome-scale...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1117907109

    authors: Nogales J,Gudmundsson S,Knight EM,Palsson BO,Thiele I

    更新日期:2012-02-14 00:00:00

  • Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells.

    abstract::Engaging mammalian Toll-like receptors (TLRs) activate both the NF-kappaB and mitogen-activated protein kinase signaling pathways. Here we establish that mitogen-activated protein 3 kinase Tpl2, levels of which are markedly reduced in nfkb1(-/-) cells, is required for extracellular signal-regulated kinase (ERK) activa...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0511113103

    authors: Banerjee A,Gugasyan R,McMahon M,Gerondakis S

    更新日期:2006-02-28 00:00:00

  • Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases.

    abstract::Guanine nucleotide-binding regulatory protein (G protein)-coupled receptor kinases (GRKs) constitute a family of serine/threonine kinases that play a major role in the agonist-induced phosphorylation and desensitization of G-protein-coupled receptors. Herein we describe the generation of monoclonal antibodies (mAbs) t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.93.15.7649

    authors: Oppermann M,Diversé-Pierluissi M,Drazner MH,Dyer SL,Freedman NJ,Peppel KC,Lefkowitz RJ

    更新日期:1996-07-23 00:00:00

  • Tradeoffs between immune function and childhood growth among Amazonian forager-horticulturalists.

    abstract::Immune function is an energetically costly physiological activity that potentially diverts calories away from less immediately essential life tasks. Among developing organisms, the allocation of energy toward immune function may lead to tradeoffs with physical growth, particularly in high-pathogen, low-resource enviro...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 临床试验,杂志文章,多中心研究

    doi:10.1073/pnas.1717522115

    authors: Urlacher SS,Ellison PT,Sugiyama LS,Pontzer H,Eick G,Liebert MA,Cepon-Robins TJ,Gildner TE,Snodgrass JJ

    更新日期:2018-04-24 00:00:00

  • Defining functional distance using manifold embeddings of gene ontology annotations.

    abstract::Although rigorous measures of similarity for sequence and structure are now well established, the problem of defining functional relationships has been particularly daunting. Here, we present several manifold embedding techniques to compute distances between Gene Ontology (GO) functional annotations and consequently e...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0702965104

    authors: Lerman G,Shakhnovich BE

    更新日期:2007-07-03 00:00:00

  • Genome analysis of Bifidobacterium bifidum PRL2010 reveals metabolic pathways for host-derived glycan foraging.

    abstract::The human intestine is densely populated by a microbial consortium whose metabolic activities are influenced by, among others, bifidobacteria. However, the genetic basis of adaptation of bifidobacteria to the human gut is poorly understood. Analysis of the 2,214,650-bp genome of Bifidobacterium bifidum PRL2010, a stra...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1011100107

    authors: Turroni F,Bottacini F,Foroni E,Mulder I,Kim JH,Zomer A,Sánchez B,Bidossi A,Ferrarini A,Giubellini V,Delledonne M,Henrissat B,Coutinho P,Oggioni M,Fitzgerald GF,Mills D,Margolles A,Kelly D,van Sinderen D,Ventura M

    更新日期:2010-11-09 00:00:00

  • The N-terminal amino-acid sequence of bovine proparathyroid hormone.

    abstract::Proparathyroid hormone (calcemic fraction-A) is a biosynthetic precursor of parathyroid hormone in bovine glands. Limited amounts of the isolated prohormone have been obtained for the purpose of initial structural studies. The results of automated sequence analysis on two separate preparations indicate that the N-term...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.71.3.653

    authors: Hamilton JW,Niall HD,Jacobs JW,Keutmann HT,Potts JT Jr,Cohn DV

    更新日期:1974-03-01 00:00:00

  • Structure of rat BCKD kinase: nucleotide-induced domain communication in a mitochondrial protein kinase.

    abstract::Mitochondrial protein kinases (mPKs) are molecular switches that down-regulate the oxidation of branched-chain alpha-ketoacids and pyruvate. Elevated levels of these metabolites are implicated in disease states such as insulin-resistant Type II diabetes, branched-chain ketoaciduria, and primary lactic acidosis. We rep...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.201220098

    authors: Machius M,Chuang JL,Wynn RM,Tomchick DR,Chuang DT

    更新日期:2001-09-25 00:00:00

  • Urocanic acid is a major chemoattractant for the skin-penetrating parasitic nematode Strongyloides stercoralis.

    abstract::Host-seeking behavior by parasitic nematodes relies heavily on chemical cues emanating from potential hosts. Nonspecific cues for Strongyloides stercoralis, a nematode that infects humans and a few other mammals, include carbon dioxide and sodium chloride; however, the characteristic species specificity of this parasi...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0610193104

    authors: Safer D,Brenes M,Dunipace S,Schad G

    更新日期:2007-01-30 00:00:00

  • The same 50-kDa cellular protein binds to the negative regulatory elements of the interleukin 2 receptor alpha-chain gene and the human immunodeficiency virus type 1 long terminal repeat.

    abstract::We have investigated the biochemical basis for negative regulation of interleukin 2 receptor alpha-chain (IL-2R alpha) gene expression. Transient transfection studies employing internally deleted forms of the IL-2R alpha promoter localized a negative regulatory element (NRE) between nucleotides -400 and -368 relative ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.86.21.8526

    authors: Smith MR,Greene WC

    更新日期:1989-11-01 00:00:00

  • Agrobacterium-delivered VirE2 interacts with host nucleoporin CG1 to facilitate the nuclear import of VirE2-coated T complex.

    abstract::Agrobacterium tumefaciens is the causal agent of crown gall disease. The bacterium is capable of transferring a segment of single-stranded DNA (ssDNA) into recipient cells during the transformation process, and it has been widely used as a genetic modification tool for plants and nonplant organisms. Transferred DNA (T...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2009645117

    authors: Li X,Yang Q,Peng L,Tu H,Lee LY,Gelvin SB,Pan SQ

    更新日期:2020-10-20 00:00:00

  • Relaxin binding in the rat heart atrium.

    abstract::Relaxin is a member of the insulin family of polypeptides that is best known as a reproductive hormone. In an effort to elucidate the mechanism of action of relaxin we previously localized the specific binding sites of a 32P-labeled relaxin in the rat uterus and brain. These studies suggested that, in addition to its ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.89.6.2384

    authors: Osheroff PL,Cronin MJ,Lofgren JA

    更新日期:1992-03-15 00:00:00

  • Aging and resistance to oxidative damage in Caenorhabditis elegans.

    abstract::The dauer larva state and the age-1 mutation, both of which extend life-span in Caenorhabditis elegans, were tested for hyperresistance to cellular damage that may be relevant to aging. The age-1 strain TJ401 displayed hyperresistance to oxidative stress relative to its parental strain. The activities of two enzymes t...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.90.19.8905

    authors: Larsen PL

    更新日期:1993-10-01 00:00:00

  • Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons.

    abstract::Mitochondrial dysfunction is implicated in the pathophysiology of Parkinson's disease (PD), a common age-associated neurodegenerative disease characterized by intraneuronal inclusions (Lewy bodies) and progressive degeneration of the nigrostriatal dopamine (DA) system. It has recently been demonstrated that midbrain D...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.0605208103

    authors: Ekstrand MI,Terzioglu M,Galter D,Zhu S,Hofstetter C,Lindqvist E,Thams S,Bergstrand A,Hansson FS,Trifunovic A,Hoffer B,Cullheim S,Mohammed AH,Olson L,Larsson NG

    更新日期:2007-01-23 00:00:00

  • Selection on phenotypic plasticity favors thermal canalization.

    abstract::Climate change affects organisms worldwide with profound ecological and evolutionary consequences, often increasing population extinction risk. Climatic factors can increase the strength, variability, or direction of natural selection on phenotypic traits, potentially driving adaptive evolution. Phenotypic plasticity ...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.2012454117

    authors: Svensson EI,Gomez-Llano M,Waller JT

    更新日期:2020-11-24 00:00:00

  • Extracellular reduction of uranium via Geobacter conductive pili as a protective cellular mechanism.

    abstract::The in situ stimulation of Fe(III) oxide reduction by Geobacter bacteria leads to the concomitant precipitation of hexavalent uranium [U(VI)] from groundwater. Despite its promise for the bioremediation of uranium contaminants, the biological mechanism behind this reaction remains elusive. Because Fe(III) oxide reduct...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1108616108

    authors: Cologgi DL,Lampa-Pastirk S,Speers AM,Kelly SD,Reguera G

    更新日期:2011-09-13 00:00:00

  • Toddlers and infants expect individuals to refrain from helping an ingroup victim's aggressor.

    abstract::Adults and older children are more likely to punish a wrongdoer for a moral transgression when the victim belongs to their group. Building on these results, in violation-of-expectation experiments (n = 198), we examined whether 2.5-year-old toddlers (Exps. 1 and 2) and 1-year-old infants (Exps. 3 and 4) would selectiv...

    journal_title:Proceedings of the National Academy of Sciences of the United States of America

    pub_type: 杂志文章

    doi:10.1073/pnas.1817849116

    authors: Ting F,He Z,Baillargeon R

    更新日期:2019-03-26 00:00:00