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    Endothelial Depletion of Murine SRF/MRTF Provokes Intracerebral Hemorrhagic Stroke (2015)

    Art
    Zeitschriftenartikel / wissenschaftlicher Beitrag
    Autoren
    Weinl, Christine
    Castaneda Vega, Salvador
    Riehle, Heidemarie
    Stritt, Christine
    Calaminus, Carsten
    Wolburg, Hartwig
    Mauel, Susanne
    Breithaupt, Angele (WE 12)
    Gruber, Achim D (WE 12)
    Wasylyk, Bohdan
    Olson, Eric N
    Adams, Ralf H
    Pichler, Bernd J
    Nordheim, Alfred
    Quelle
    Proceedings of the National Academy of Sciences of the United States of America; 112(32) — S. 9914–9919
    ISSN: 0027-8424
    Sprache
    Englisch
    Verweise
    DOI: 10.1073/pnas.1509047112
    Pubmed: 26221020
    Kontakt
    Institut für Tierpathologie

    Robert-von-Ostertag-Str. 15
    Gebäude 12
    14163 Berlin
    +49 30 838 62450

    Abstract / Zusammenfassung

    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.