Impaired meningeal lymphatic vessel development worsens stroke outcome

Pavel Yanev, Katherine Poinsatte, Devon Hominick, Noor Khurana, Kielen R. Zuurbier, Marcus Berndt, Erik J. Plautz, Michael T. Dellinger, Ann M. Stowe

Research output: Contribution to journalArticlepeer-review

43 Scopus citations

Abstract

The discovery of meningeal lymphatic vessels (LVs) has sparked interest in identifying their role in diseases of the central nervous system. Similar to peripheral LVs, meningeal LVs depend on vascular endothelial growth factor receptor-3 (VEGFR3) signaling for development. Here we characterize the effect of stroke on meningeal LVs, and the impact of meningeal lymphatic hypoplasia on post-stroke outcomes. We show that photothrombosis (PT), but not transient middle cerebral artery occlusion (tMCAo), induces meningeal lymphangiogenesis in young male C57Bl/J6 mice. We also show that Vegfr3wt/mut mice develop significantly fewer meningeal LVs than Vegfr3wt/wt mice. Again, meningeal lymphangiogenesis occurs in the alymphatic zone lateral to the sagittal sinus only after PT-induced stroke in Vegfr3wt/wt mice. Interestingly, Vegfr3wt/mut mice develop larger stroke volumes than Vegfr3wt/wt mice after tMCAo, but not after PT. Our results reveal differences between PT and tMCAo models of stroke and underscore the need to consider method of stroke induction when investigating the role of meningeal lymphatics. Taken together, our data indicate that ischemic injury can induce the growth of meningeal LVs and that the absence of these LVs can impact post-stroke outcomes.

Original languageEnglish
Pages (from-to)263-275
Number of pages13
JournalJournal of Cerebral Blood Flow and Metabolism
Volume40
Issue number2
DOIs
StatePublished - Feb 1 2020

Bibliographical note

Funding Information:
We thank the UT Southwestern Whole Brain Microscopy Facility (WBMF) in the department of Neurology and Neurotherapeutics for assistance with serial two-photon tomography. We would also like to acknowledge the contributions of the UT Southwestern Neuromodels Facility for PT and tMCAo surgeries and post-operative care. The C3H101H-Flt4Chy/H (VEGFR3) mice were obtained from the MRC Harwell which distributes this strain on behalf of the European Mouse Mutant Archive (EMMA: www.infrafrontier.eu). The repository number is EM:00068. The C3H101H-Flt4Chy/H (VEGFR3) mice were originally generated at the MRC-Harwell.

Publisher Copyright:
© The Author(s) 2019.

Keywords

  • Stroke
  • VEGFR3
  • lymphangiogenesis
  • meningeal lymphatics

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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