Endoglin haplo-insufficiency modifies the inflammatory response in irradiated mouse hearts without affecting structural and mircovascular changes

• Published in: PloS one Vol. 8; no. 7; p. e68922
• Main Authors: Seemann, Ingar, Te Poele, Johannes A M, Luikinga, Sophia J, Hoving, Saske, Stewart, Fiona A
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 24.07.2013; Public Library of Science (PLoS)
• Subjects: Alkaline phosphatase; Angiogenesis; Animals; Biology; Cancer therapies; Cardiovascular diseases; CD45 antigen; Cell growth; Cell proliferation; Collagen; Computed tomography; Damage assessment; Damage detection; DNA microarrays; Dose-Response Relationship, Radiation; Emission measurements; Endoglin; Endothelial cells; Experiments; Extracellular matrix; Fibrosis; Gene expression; Gene Expression Profiling; Genes; Growth factors; Health risks; Heart; Heart - radiation effects; Heart diseases; Histochemistry; Immunology; Inflammatory response; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Irradiated; Irradiation; Kinases; Laboratory animals; Male; Mathematical morphology; Medicine; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microvasculature; Photon emission; Platelet-derived growth factor; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Radiation; Radiation damage; Radiation dosage; Radiation effects; Radiation therapy; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Signal transduction; Single photon emission computed tomography; Stress response; Thorax; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; Tumors; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068922

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. 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). 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. 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.