TY - JOUR
T1 - Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke
AU - Weinl, Christine
AU - Vega, Salvador Castaneda
AU - Riehle, Heidemarie
AU - Stritt, Christine
AU - Calaminus, Carsten
AU - Wolburg, Hartwig
AU - Mauel, Susanne
AU - Breithaupt, Angele
AU - Gruber, Achim D.
AU - Wasylyk, Bohdan
AU - Olson, Eric N.
AU - Adams, Ralf H.
AU - Pichler, Bernd J.
AU - Nordheim, Alfred
PY - 2015/8/11
Y1 - 2015/8/11
N2 - 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.
AB - 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.
KW - Blood-brain barrier
KW - Cerebral microbleeds
KW - Conditional gene knockout
KW - Stroke mouse model
KW - Transcription
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U2 - 10.1073/pnas.1509047112
DO - 10.1073/pnas.1509047112
M3 - Article
C2 - 26221020
AN - SCOPUS:84938934782
SN - 0027-8424
VL - 112
SP - 9914
EP - 9919
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 32
ER -