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

Abstract

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.