Mechanisms of cardiac endothelial damage by ionising radiation

Exposure of the heart to ionising radiation even at low to moderate doses can increase the risk of developing cardiovascular disease (CVD) many years later. This is of significance to cancer survivors who were treated with radiotherapy in the thorax. Damage to the heart microvasculature is thought to play a key role in development of radiation-induced CVD. The aim of this project was to investigate the effects of radiation on heart microvascular endothelial function using in vitro and in vivo approaches. In particular effects of radiation on angiogenesis were investigated since angiogenesis is important for heart repair after myocardial injury. The hearts of C57BL/6 and APOE-/- mice were X-ray irradiated with doses of 0.2 to 16 Gray by the group’s collaborators and animals were sacrificed at 20-60 weeks post-irradiation. Angiogenic sprouting was assessed in heart explants embedded in fibrin. A dose dependent reduction in angiogenic sprouting was observed, which was significant after ≥8 Gy at 20 weeks and ≥2 Gy at 60 weeks post-irradiation demonstrating that vascular damage was progressive. Radiation inhibited in vitro endothelial migration at doses of ≥0.2 Gy. Radiation also inhibited endothelial tubule formation in matrigel and in organotypic assays in which endothelial cells were co-cultured with fibroblasts. In addition to damaging cells directly, radiation also induces indirect effects through bystander interactions. Results showed that irradiated fibroblasts inhibited angiogenesis through soluble factors they secreted into their conditioned media. Signaling mechanisms through which radiation alters angiogenic function were studied. Results showed that transforming growth factor beta and Rho-GTPase signaling are involved in the anti-angiogenic activity of radiation. In summary, this study established that low to moderate doses of radiation inhibit endothelial function which could contribute to the development of CVD. The study also identified signaling pathways that may be targeted to protect against radiation-induced heart microvascular damage.