Entwicklung und Evaluierung neuer niedrig-molekularer Sonden für die Charakterisierung von Gefäßerkrankungen mittels der Magnetresonanztomographie
Final Report Abstract
The main findings of this project were: • It could be shown that the in vivo assessment of the arterial vessel wall on a molecular level allowed a biological characterisation of early pathological vessel wall changes and thereby improve the staging of vascular diseases and enable more accurate monitoring of therapy response. • To extend the classical single-probe approach in MR imaging, a simultaneous dual-probe approach for the assessment of ECM proteins and inflammatory activity within a single MR session was investigated. • Using this multi-probe molecular MRI approach in mouse-model of progressive atherosclerosis, the temporal association between intraplaque inflammation and remodeling of elastic fibers of the ECM could be investigated for the first time in a single scan. • The in vivo dual-probe imaging of murine AAAs using an elastin / collagenspecific probe simultaneously with iron oxide particles enabled an accurate monitoring of dissecting AAA development in different stages of the disease. Moreover, combining an ECM protein-specific and an inflammation-specific probe, the rupture of murine AAAs could be predicted with a higher diagnostic accuracy compared to using a classical single probe alone. • An interesting and surprising part of this project arose in the context of investigating the role of biglycan in the context of atherosclerosis ex vivo. Here we also focused on its main aggrecanases ADAMTS-4, which has biglycan as its substrate. • While investigating ADAMTS-4 in different stages of the atherosclerotic plaque in our mouse model, we found that the differences in expression of ADAMTS-4 between early and advanced atherosclerotic plaque was significantly higher compared to differences measured for biglycan. ADAMTS-4 therefore represents a more promising imaging biomarker for the development of advanced atherosclerotic plaque. We therefore shifted the focus of this subproject on the development of an ADAMTS-4 specific MR probe. Overall, this project contributed to the understanding of the role of the extracellular matrix and proinflammatory macrophages during the development of atherosclerotic plaque and aortic aneurysms. Especially the multi-probe molecular MRI approach enables the simultaneous assessment of matrix remodeling and inflammatory activity during the development of different stages of vascular diseases. These new imaging parameters may complement already established morphological parameters, such as the vascular diameter, and may therefore improve especially the prediction of risk of aortic and plaque rupture.
Publications
- Molecular Imaging of Abdominal Aortic Aneurysms. Trends in Molecular Medicine, Vol. 23. 2017, Issue 2, pp. 150-164.
Brangsch J., Reimann C., Collettini F., Buchert R., Botnar R.M., Makowski M.R.
(See online at https://doi.org/10.1016/j.molmed.2016.12.002) - Molecular imaging of the extracellular matrix in the context of atherosclerosis. Advanced Drug Delivery Reviews, Vol. 113. 2017, pp. 49-60.
Reimann C., Brangsch J., Colletini F., Walter T., Hamm B., Botnar R.M., Makowski M.R.
(See online at https://doi.org/10.1016/j.addr.2016.09.005) - Contrast-Enhanced Magnetic Resonance Angiography Using a Novel Elastin-Specific Molecular Probe in an Experimental Animal Model. Contrast Media & Molecular Imaging, Vol. 2018, Article ID 9217456.
Reimann C., Brangsch J., Kaufmann J.O., Adams L.C., Onthank D.C., Robinson S.P., Botnar R.M., Collettini F., Makowski M.R.
(See online at https://doi.org/10.1155/2018/9217456) - Concurrent Molecular Magnetic Resonance Imaging of Inflammatory Activity and Extracellular Matrix Degradation for the Prediction of Aneurysm Rupture.
Circulation: Cardiovascular Imaging, Vol. 12. 2019, Issue 3: e008707.
Brangsch J., Reimann C., Kaufmann J.O., Adams L.C., Onthank D.C., Thone-Reineke C., Robinson S.P., Buchholz R., Karst U., Botnar R.M., Hamm B., Makowski M.R.
(See online at https://doi.org/10.1161/CIRCIMAGING.118.008707) - Dual-probe molecular MRI for the in vivo characterization of atherosclerosis in a mouse model: Simultaneous assessment of plaque inflammation and extracellular-matrix remodeling. Scientific Reports, Vol. 9. 2019, Article number: 13827.
Reimann C., Brangsch J., Kaufmann J.O., Adams L.C., Onthank D.C., Thöne-Reineke C., Robinson S.P., Hamm B., Botnar R.M., Makowski M.R.
(See online at https://doi.org/10.1038/s41598-019-50100-8) - Molecular MR-imaging for the noninvasive quantification of the anti-inflammatory effects of targeting interleukin-1β in a mouse model of aortic aneurysm. Molecular Imaging, Vol. 19.2020: 1536012120961875.
Brangsch J., Reimann C., Kaufmann J.O., Adams L.C., Onthank D.C., Thone-Reineke C., Robinson S.P., Wilke M., Weller M., Buchholz R., Karst U., Botnar R.M., Hamm B., Makowski M.R.
(See online at https://doi.org/10.1177/1536012120961875) - Noninvasive imaging of vascular permeability to predict the risk of rupture in abdominal aortic aneurysms using an albumin-binding probe. Scientific Reports, Vol. 10. 2020, Article number: 3231.
Adams L.C., Brangsch J., Reimann C., Kaufmann J.O., Nowak K., Buchholz R., Karst U., Botnar R.M., Hamm B., Makowski M.R.
(See online at https://doi.org/10.1038/s41598-020-59842-2) - Simultaneous molecular MRI of extracellular matrix collagen and inflammatory activity to predict abdominal aortic aneurysm rupture. Scientific Reports, Vol. 10. 2020, Article number: 15206.
Adams L.C., Reimann C., Brangsch J., Kaufmann J.O., Buchholz R., Karst U., Botnar R.M., Hamm B., Makowski M.R.
(See online at https://doi.org/10.1038/s41598-020-71817-x)
