title: Endoglin haplo-insufficiency modifies the inflammatory response in irradiated mouse hearts without affecting structural and mircovascular changes.
abstract: BACKGROUND
  It is now widely recognized that radiotherapy of thoracic and chest wall tumors increases the long-term risk of cardiovascular damage although the underlying mechanisms are not fully elucidated. There is increasing evidence that microvascular damage is involved. Endoglin, an accessory receptor for TGF-β1, is highly expressed in damaged endothelial cells and may play a crucial role in cell proliferation and revascularization of damaged heart tissue. We have therefore specifically examined the role of endoglin in microvascular damage and repair in the irradiated heart.
  
  
  METHODS
  A single dose of 16 Gy was delivered to the heart of adult Eng(+/+) or Eng(+/-) mice and damage was evaluated at 4, 20 and 40 weeks, relative to age-matched controls. Gated single photon emission computed tomography (gSPECT) was used to measure cardiac geometry and function, and related to histo-morphology, microvascular damage (detected using immuno- and enzyme-histochemistry) and gene expression (detected by microarray and real time PCR).
  
  
  RESULTS
  Genes categorized according to known inflammatory and immunological related disease were less prominently regulated in irradiated Eng(+/-) mice compared to Eng(+/+) littermates. Fibrosis related genes, TGF-β1, ALK 5 and PDGF, were only upregulated in Eng(+/+) mice during the early phase of radiation-induced cardiac damage (4 weeks). In addition, only the Eng(+/+) mice showed significant upregulation of collagen deposition in the early fibrotic phase (20 weeks) after irradiation. Despite these differences in gene expression, there was no reduction in inflammatory invasion (CD45+cells) of irradiated Eng(+/-) hearts. Microvascular damage (microvascular density, alkaline phosphatase and von-Willebrand-Factor expression) was also similar in both strains.
  
  
  CONCLUSIONS
  Eng(+/-) mice displayed impaired early inflammatory and fibrotic responses to high dose irradiation compared to Eng(+/+) littermates. This did not result in significant differences in microvascular damage or cardiac function between the strains.
authors.affiliation: Division of Biological Stress Response, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Ingar
authors.initials: I
authors.lastname: Seemann
authors.forename: Johannes A M
authors.initials: JA
authors.lastname: Te Poele
authors.forename: Sophia J
authors.initials: SJ
authors.lastname: Luikinga
authors.forename: Saske
authors.initials: S
authors.lastname: Hoving
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Stewart
mesh_terms: D000818:Animals; D004307:Dose-Response Relationship, Radiation; D000071063:Endoglin; D020869:Gene Expression Profiling; D006321:Heart / Q000528:radiation effects*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000071063:Endoglin; C502004:Eng protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D018125:Receptors, Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse
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