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  • Mäe, Maarja AndaloussiUppsala universitet,Vaskulärbiologi (författare)

Single-Cell Analysis of Blood-Brain Barrier Response to Pericyte Loss

  • Artikel/kapitelEngelska2021

Förlag, utgivningsår, omfång ...

  • Lippincott Williams & Wilkins,2021
  • printrdacarrier

Nummerbeteckningar

  • LIBRIS-ID:oai:DiVA.org:uu-442608
  • https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-442608URI
  • https://doi.org/10.1161/CIRCRESAHA.120.317473DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:146440624URI

Kompletterande språkuppgifter

  • Språk:engelska
  • Sammanfattning på:engelska

Ingår i deldatabas

Klassifikation

  • Ämneskategori:ref swepub-contenttype
  • Ämneskategori:art swepub-publicationtype

Anmärkningar

  • Rationale: Pericytes are capillary mural cells playing a role in stabilizing newly formed blood vessels during development and tissue repair. Loss of pericytes has been described in several brain disorders, and genetically induced pericyte deficiency in the brain leads to increased macromolecular leakage across the blood-brain barrier (BBB). However, the molecular details of the endothelial response to pericyte deficiency remain elusive.Objective: To map the transcriptional changes in brain endothelial cells resulting from lack of pericyte contact at single-cell level and to correlate them with regional heterogeneities in BBB function and vascular phenotype.Methods and Results: We reveal transcriptional, morphological, and functional consequences of pericyte absence for brain endothelial cells using a combination of methodologies, including single-cell RNA sequencing, tracer analyses, and immunofluorescent detection of protein expression in pericyte-deficient adult Pdgfb(ret/ret) mice. We find that endothelial cells without pericyte contact retain a general BBB-specific gene expression profile, however, they acquire a venous-shifted molecular pattern and become transformed regarding the expression of numerous growth factors and regulatory proteins. Adult Pdgfb(ret/ret) brains display ongoing angiogenic sprouting without concomitant cell proliferation providing unique insights into the endothelial tip cell transcriptome. We also reveal heterogeneous modes of pericyte-deficient BBB impairment, where hotspot leakage sites display arteriolar-shifted identity and pinpoint putative BBB regulators. By testing the causal involvement of some of these using reverse genetics, we uncover a reinforcing role for angiopoietin 2 at the BBB.Conclusions: By elucidating the complexity of endothelial response to pericyte deficiency at cellular resolution, our study provides insight into the importance of brain pericytes for endothelial arterio-venous zonation, angiogenic quiescence, and a limited set of BBB functions. The BBB-reinforcing role of ANGPT2 (angiopoietin 2) is paradoxical given its wider role as TIE2 (TEK receptor tyrosine kinase) receptor antagonist and may suggest a unique and context-dependent function of ANGPT2 in the brain.

Ämnesord och genrebeteckningar

Biuppslag (personer, institutioner, konferenser, titlar ...)

  • He, LiqunUppsala universitet,Vaskulärbiologi,Tianjin Med Univ, Tianjin Neurol Inst, Key Lab Postneuroinjury Neurorepair & Regenerat, Neurosurg,Gen Hosp,Minist Educ, Tianjin, Peoples R China.(Swepub:uu)liqhe592 (författare)
  • Nordling, Sofia,1985-Uppsala universitet,Vaskulärbiologi,Stanford Univ, Sch Med, Pathol, Stanford, CA USA.(Swepub:uu)sofno833 (författare)
  • Vazquez-Liebanas, ElisaUppsala universitet,Vaskulärbiologi(Swepub:uu)eliva388 (författare)
  • Nahar, KhayrunUppsala universitet,Vaskulärbiologi(Swepub:uu)khana914 (författare)
  • Jung, BongnamUppsala universitet,Institutionen för immunologi, genetik och patologi,Harvard Med Sch, Dept Surg, Boston, MA USA. (författare)
  • Li, XidanKarolinska Inst, Integrated Cardio Metab Ctr ICMC, Campus Flemingsberg, Solna, Sweden.;Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, Solna, Sweden. (författare)
  • Tan, Bryan C.Duke NUS Med Sch, Singapore, Singapore. (författare)
  • Foo, Juat ChinNatl Univ Singapore, Life Sci Inst, Singapore Lipid Incubator SLING, Singapore, Singapore. (författare)
  • Cazenave-Gassiot, AmauryNatl Univ Singapore, Life Sci Inst, Singapore Lipid Incubator SLING, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med AC G, Biochem, Singapore, Singapore. (författare)
  • Wenk, Markus R.Natl Univ Singapore, Life Sci Inst, Singapore Lipid Incubator SLING, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med AC G, Biochem, Singapore, Singapore. (författare)
  • Zarb, YvetteLudwig Maximilians Univ Munchen, Inst Physiol, Munich, Germany.;Zurich Univ, Zurich Univ Hosp, Clin Neurosci Ctr, Zurich, Switzerland. (författare)
  • Laviña, BàrbaraUppsala universitet,Vaskulärbiologi(Swepub:uu)barsi852 (författare)
  • Quaggin, Susan E.Northwestern Univ, Feinberg Sch Med, Med, Chicago, IL USA. (författare)
  • Jeansson, MarieKarolinska Institutet,Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Integrated Cardio Metab Ctr ICMC, Campus Flemingsberg, Solna, Sweden.;Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, Solna, Sweden.(Swepub:uu)marje618 (författare)
  • Gu, ChenguaHarvard Med Sch, Neurobiol, Boston, MA 02115 USA. (författare)
  • Silver, David L.Duke NUS Med Sch, Singapore, Singapore. (författare)
  • Vanlandewijck, Michael,1982-Uppsala universitet,Vaskulärbiologi,Karolinska Inst, Integrated Cardio Metab Ctr ICMC, Campus Flemingsberg, Solna, Sweden.;Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, Solna, Sweden.(Swepub:uu)micva660 (författare)
  • Butcher, Eugene C.Stanford Univ, Sch Med, Pathol, Stanford, CA USA. (författare)
  • Keller, AnnikaZurich Univ, Zurich Univ Hosp, Clin Neurosci Ctr, Zurich, Switzerland. (författare)
  • Betsholtz, ChristerUppsala universitet,Vaskulärbiologi,Karolinska Inst, Integrated Cardio Metab Ctr ICMC, Campus Flemingsberg, Solna, Sweden.;Karolinska Inst, Dept Med Huddinge, Campus Flemingsberg, Solna, Sweden.(Swepub:uu)chbet517 (författare)
  • Uppsala universitetVaskulärbiologi (creator_code:org_t)

Sammanhörande titlar

  • Ingår i:Circulation Research: Lippincott Williams & Wilkins128:4, s. E46-E620009-73301524-4571

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