Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke

Christine Weinl, Salvador Castaneda Vega, Heidemarie Riehle, Christine Stritt, Carsten Calaminus, Hartwig Wolburg, Susanne Mauel, Angele Breithaupt, Achim D. Gruber, Bohdan Wasylyk, Eric N. Olson, Ralf H. Adams, Bernd J. Pichler, Alfred Nordheim

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Intracerebral hemorrhagic stroke and vascular dementia are ageand 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 ECspecific 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.

Original languageEnglish (US)
Pages (from-to)9914-9919
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number32
DOIs
StatePublished - Aug 11 2015

Keywords

  • Blood-brain barrier
  • Cerebral microbleeds
  • Conditional gene knockout
  • Stroke mouse model
  • Transcription

ASJC Scopus subject areas

  • General

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    Weinl, C., Vega, S. C., Riehle, H., Stritt, C., Calaminus, C., Wolburg, H., Mauel, S., Breithaupt, A., Gruber, A. D., Wasylyk, B., Olson, E. N., Adams, R. H., Pichler, B. J., & Nordheim, A. (2015). Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke. Proceedings of the National Academy of Sciences of the United States of America, 112(32), 9914-9919. https://doi.org/10.1073/pnas.1509047112