Ephrin-B2 reverse signaling increases α5β1 integrin-mediated fibronectin deposition and reduces distal lung compliance

Katherine M. Bennett, Maria D. Afanador, Charitharth V. Lal, Haiming Xu, Elizabeth Persad, Susan K. Legan, George Chenaux, Michael Dellinger, Rashmin C. Savani, Christopher Dravis, Mark Henkemeyer, Margaret Schwarz

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Alveolar growth abnormalities and severe respiratory dysfunction are often fatal. Identifying mechanisms that control epithelial proliferation and enlarged, poorly septated airspaces is essential in developing new therapies for lung disease. The membrane-bound ligand ephrin-B2 is strongly expressed in lung epithelium, and yet in contrast to its known requirement for arteriogenesis, considerably less isknownregarding the function of this protein in the epithelium. We hypothesize that the vascular mediator ephrin-B2 governs alveolar growth and mechanics beyond the confines of the endothelium. We used the in vivo manipulation of ephrin-B2 reverse signaling to determine the role of this vascularmediator in thepulmonary epithelium and distal lung mechanics. We determined that the ephrin-B2 gene (EfnB2) is strongly expressed in alveolar Type 2 cells throughout development and into adulthood. The role of ephrin-B2 reverse signaling in the lung was assessed in Efnb2LacZ/6YFDV mutants that coexpress the intracellular truncated ephrin-B2-β-galactosidase fusion and an intracellular point mutant ephrin-B2 protein that is unable to become tyrosine-phosphorylated or to interact with either the SH2 or PDZ domain-containing downstream signaling proteins. In these viable mice, we observed pulmonary hypoplasia and altered pulmonary mechanics, as evidenced by a marked reduction in lung compliance. Associated with the reduction in lung compliance was a significant increase in insoluble fibronectin (FN) basement membrane matrix assembly with FN deposition, and a corresponding increase in the α5 integrin receptor required for FN fibrillogenesis. These experiments indicate that ephrin-B2 reverse signaling mediates distal alveolar formation, fibrillogenesis, and pulmonary compliance.

Original languageEnglish (US)
Pages (from-to)680-687
Number of pages8
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume49
Issue number4
DOIs
StatePublished - Oct 2013
Externally publishedYes

Fingerprint

Ephrin-B2
Lung Compliance
Fibronectins
Integrins
Lung
Mechanics
Epithelium
Galactosidases
Integrin alpha5beta1
PDZ Domains
Pulmonary diseases
Proteins
src Homology Domains
Compliance
Growth
Basement Membrane
Lung Diseases
Endothelium
Blood Vessels
Tyrosine

Keywords

  • α5β1 integrin
  • Alveoli
  • Arterial
  • Fibronectin
  • Pulmonary mechanics

ASJC Scopus subject areas

  • Cell Biology
  • Pulmonary and Respiratory Medicine
  • Molecular Biology
  • Clinical Biochemistry

Cite this

Ephrin-B2 reverse signaling increases α5β1 integrin-mediated fibronectin deposition and reduces distal lung compliance. / Bennett, Katherine M.; Afanador, Maria D.; Lal, Charitharth V.; Xu, Haiming; Persad, Elizabeth; Legan, Susan K.; Chenaux, George; Dellinger, Michael; Savani, Rashmin C.; Dravis, Christopher; Henkemeyer, Mark; Schwarz, Margaret.

In: American Journal of Respiratory Cell and Molecular Biology, Vol. 49, No. 4, 10.2013, p. 680-687.

Research output: Contribution to journalArticle

Bennett, KM, Afanador, MD, Lal, CV, Xu, H, Persad, E, Legan, SK, Chenaux, G, Dellinger, M, Savani, RC, Dravis, C, Henkemeyer, M & Schwarz, M 2013, 'Ephrin-B2 reverse signaling increases α5β1 integrin-mediated fibronectin deposition and reduces distal lung compliance', American Journal of Respiratory Cell and Molecular Biology, vol. 49, no. 4, pp. 680-687. https://doi.org/10.1165/rcmb.2013-0002OC
Bennett, Katherine M. ; Afanador, Maria D. ; Lal, Charitharth V. ; Xu, Haiming ; Persad, Elizabeth ; Legan, Susan K. ; Chenaux, George ; Dellinger, Michael ; Savani, Rashmin C. ; Dravis, Christopher ; Henkemeyer, Mark ; Schwarz, Margaret. / Ephrin-B2 reverse signaling increases α5β1 integrin-mediated fibronectin deposition and reduces distal lung compliance. In: American Journal of Respiratory Cell and Molecular Biology. 2013 ; Vol. 49, No. 4. pp. 680-687.
@article{c3a2972336db4d1289e2d9d5c4aeee5b,
title = "Ephrin-B2 reverse signaling increases α5β1 integrin-mediated fibronectin deposition and reduces distal lung compliance",
abstract = "Alveolar growth abnormalities and severe respiratory dysfunction are often fatal. Identifying mechanisms that control epithelial proliferation and enlarged, poorly septated airspaces is essential in developing new therapies for lung disease. The membrane-bound ligand ephrin-B2 is strongly expressed in lung epithelium, and yet in contrast to its known requirement for arteriogenesis, considerably less isknownregarding the function of this protein in the epithelium. We hypothesize that the vascular mediator ephrin-B2 governs alveolar growth and mechanics beyond the confines of the endothelium. We used the in vivo manipulation of ephrin-B2 reverse signaling to determine the role of this vascularmediator in thepulmonary epithelium and distal lung mechanics. We determined that the ephrin-B2 gene (EfnB2) is strongly expressed in alveolar Type 2 cells throughout development and into adulthood. The role of ephrin-B2 reverse signaling in the lung was assessed in Efnb2LacZ/6YFDV mutants that coexpress the intracellular truncated ephrin-B2-β-galactosidase fusion and an intracellular point mutant ephrin-B2 protein that is unable to become tyrosine-phosphorylated or to interact with either the SH2 or PDZ domain-containing downstream signaling proteins. In these viable mice, we observed pulmonary hypoplasia and altered pulmonary mechanics, as evidenced by a marked reduction in lung compliance. Associated with the reduction in lung compliance was a significant increase in insoluble fibronectin (FN) basement membrane matrix assembly with FN deposition, and a corresponding increase in the α5 integrin receptor required for FN fibrillogenesis. These experiments indicate that ephrin-B2 reverse signaling mediates distal alveolar formation, fibrillogenesis, and pulmonary compliance.",
keywords = "α5β1 integrin, Alveoli, Arterial, Fibronectin, Pulmonary mechanics",
author = "Bennett, {Katherine M.} and Afanador, {Maria D.} and Lal, {Charitharth V.} and Haiming Xu and Elizabeth Persad and Legan, {Susan K.} and George Chenaux and Michael Dellinger and Savani, {Rashmin C.} and Christopher Dravis and Mark Henkemeyer and Margaret Schwarz",
year = "2013",
month = "10",
doi = "10.1165/rcmb.2013-0002OC",
language = "English (US)",
volume = "49",
pages = "680--687",
journal = "American Journal of Respiratory Cell and Molecular Biology",
issn = "1044-1549",
publisher = "American Thoracic Society",
number = "4",

}

TY - JOUR

T1 - Ephrin-B2 reverse signaling increases α5β1 integrin-mediated fibronectin deposition and reduces distal lung compliance

AU - Bennett, Katherine M.

AU - Afanador, Maria D.

AU - Lal, Charitharth V.

AU - Xu, Haiming

AU - Persad, Elizabeth

AU - Legan, Susan K.

AU - Chenaux, George

AU - Dellinger, Michael

AU - Savani, Rashmin C.

AU - Dravis, Christopher

AU - Henkemeyer, Mark

AU - Schwarz, Margaret

PY - 2013/10

Y1 - 2013/10

N2 - Alveolar growth abnormalities and severe respiratory dysfunction are often fatal. Identifying mechanisms that control epithelial proliferation and enlarged, poorly septated airspaces is essential in developing new therapies for lung disease. The membrane-bound ligand ephrin-B2 is strongly expressed in lung epithelium, and yet in contrast to its known requirement for arteriogenesis, considerably less isknownregarding the function of this protein in the epithelium. We hypothesize that the vascular mediator ephrin-B2 governs alveolar growth and mechanics beyond the confines of the endothelium. We used the in vivo manipulation of ephrin-B2 reverse signaling to determine the role of this vascularmediator in thepulmonary epithelium and distal lung mechanics. We determined that the ephrin-B2 gene (EfnB2) is strongly expressed in alveolar Type 2 cells throughout development and into adulthood. The role of ephrin-B2 reverse signaling in the lung was assessed in Efnb2LacZ/6YFDV mutants that coexpress the intracellular truncated ephrin-B2-β-galactosidase fusion and an intracellular point mutant ephrin-B2 protein that is unable to become tyrosine-phosphorylated or to interact with either the SH2 or PDZ domain-containing downstream signaling proteins. In these viable mice, we observed pulmonary hypoplasia and altered pulmonary mechanics, as evidenced by a marked reduction in lung compliance. Associated with the reduction in lung compliance was a significant increase in insoluble fibronectin (FN) basement membrane matrix assembly with FN deposition, and a corresponding increase in the α5 integrin receptor required for FN fibrillogenesis. These experiments indicate that ephrin-B2 reverse signaling mediates distal alveolar formation, fibrillogenesis, and pulmonary compliance.

AB - Alveolar growth abnormalities and severe respiratory dysfunction are often fatal. Identifying mechanisms that control epithelial proliferation and enlarged, poorly septated airspaces is essential in developing new therapies for lung disease. The membrane-bound ligand ephrin-B2 is strongly expressed in lung epithelium, and yet in contrast to its known requirement for arteriogenesis, considerably less isknownregarding the function of this protein in the epithelium. We hypothesize that the vascular mediator ephrin-B2 governs alveolar growth and mechanics beyond the confines of the endothelium. We used the in vivo manipulation of ephrin-B2 reverse signaling to determine the role of this vascularmediator in thepulmonary epithelium and distal lung mechanics. We determined that the ephrin-B2 gene (EfnB2) is strongly expressed in alveolar Type 2 cells throughout development and into adulthood. The role of ephrin-B2 reverse signaling in the lung was assessed in Efnb2LacZ/6YFDV mutants that coexpress the intracellular truncated ephrin-B2-β-galactosidase fusion and an intracellular point mutant ephrin-B2 protein that is unable to become tyrosine-phosphorylated or to interact with either the SH2 or PDZ domain-containing downstream signaling proteins. In these viable mice, we observed pulmonary hypoplasia and altered pulmonary mechanics, as evidenced by a marked reduction in lung compliance. Associated with the reduction in lung compliance was a significant increase in insoluble fibronectin (FN) basement membrane matrix assembly with FN deposition, and a corresponding increase in the α5 integrin receptor required for FN fibrillogenesis. These experiments indicate that ephrin-B2 reverse signaling mediates distal alveolar formation, fibrillogenesis, and pulmonary compliance.

KW - α5β1 integrin

KW - Alveoli

KW - Arterial

KW - Fibronectin

KW - Pulmonary mechanics

UR - http://www.scopus.com/inward/record.url?scp=84886531656&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84886531656&partnerID=8YFLogxK

U2 - 10.1165/rcmb.2013-0002OC

DO - 10.1165/rcmb.2013-0002OC

M3 - Article

VL - 49

SP - 680

EP - 687

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1044-1549

IS - 4

ER -