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.Materials & 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.Conclusion: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. © 2013 Seemann et al.