title: Pericyte requirement for anti-leak action of angiopoietin-1 and vascular remodeling in sustained inflammation.
abstract: Blood vessel leakiness is an early, transient event in acute inflammation but can also persist as vessels undergo remodeling in sustained inflammation. Angiopoietin/Tie2 signaling can reduce the leakiness through changes in endothelial cells. The role of pericytes in this action has been unknown. We used the selective PDGF-B-blocking oligonucleotide aptamer AX102 to determine whether disruption of pericyte-endothelial crosstalk alters vascular leakiness or remodeling in the airways of mice under four different conditions: i) baseline, ii) acute inflammation induced by bradykinin, iii) sustained inflammation after 7-day infection by the respiratory pathogen Mycoplasma pulmonis, or iv) leakage after bradykinin challenge in the presence of vascular stabilization by the angiopoietin-1 (Ang1) mimic COMP-Ang1 for 7 days. AX102 reduced pericyte coverage but did not alter the leakage of microspheres from tracheal blood vessels at baseline or after bradykinin; however, AX102 exaggerated leakage at 7 days after M. pulmonis infection and increased vascular remodeling and disease severity at 14 days. AX102 also abolished the antileakage effect of COMP-Ang1 at 7 days. Together, these findings show that pericyte contributions to endothelial stability have greater dependence on PDGF-B during the development of sustained inflammation, when pericyte dynamics accompany vascular remodeling, than under baseline conditions or in acute inflammation. The findings also show that the antileakage action of Ang1 requires PDGF-dependent actions of pericytes in maintaining endothelial stability.
authors.affiliation: Department of Anatomy, Cardiovascular Research Institute, Comprehensive Cancer Center, University of California, San Francisco, California, USA.
authors.forename: Jonas
authors.initials: J
authors.lastname: Fuxe
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tabruyn
authors.forename: Katharine
authors.initials: K
authors.lastname: Colton
authors.forename: Harras
authors.initials: H
authors.lastname: Zaid
authors.forename: Alicia
authors.initials: A
authors.lastname: Adams
authors.forename: Peter
authors.initials: P
authors.lastname: Baluk
authors.forename: Erin
authors.initials: E
authors.lastname: Lashnits
authors.forename: Tohru
authors.initials: T
authors.lastname: Morisada
authors.forename: Tom
authors.initials: T
authors.lastname: Le
authors.forename: Shaun
authors.initials: S
authors.lastname: O'Brien
authors.forename: David M
authors.initials: DM
authors.lastname: Epstein
authors.forename: Gou Young
authors.initials: GY
authors.lastname: Koh
authors.forename: Donald M
authors.initials: DM
authors.lastname: McDonald
mesh_terms: D000199:Actins / Q000378:metabolism; D042683:Angiopoietin-1 / Q000378:metabolism*; D000818:Animals; D052157:Aptamers, Nucleotide / Q000494:pharmacology; D001920:Bradykinin / Q000494:pharmacology; D002452:Cell Count; D048430:Cell Shape / Q000187:drug effects; D003893:Desmin / Q000378:metabolism; D007249:Inflammation / Q000150:complications / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D009175:Mycoplasma Infections / Q000150:complications / Q000473:pathology; D045803:Mycoplasma pulmonis / Q000187:drug effects / Q000502:physiology; D020286:Pericytes / Q000187:drug effects / Q000382:microbiology / Q000473:pathology*; D020574:Proto-Oncogene Proteins c-sis / Q000037:antagonists & inhibitors / Q000378:metabolism; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014132:Trachea / Q000098:blood supply* / Q000382:microbiology / Q000473:pathology*
chemical_list: D000199:Actins; D042683:Angiopoietin-1; D052157:Aptamers, Nucleotide; C515576:COMP-Ang1 fusion protein; D003893:Desmin; D020574:Proto-Oncogene Proteins c-sis; D011993:Recombinant Fusion Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D001920:Bradykinin