Developmental Basis of Media Calcification

The massive burden of cardiovascular disease in chronic kidney disease and diabetes mellitus is strongly associated with extensive media calcification, reduced vascular compliance, left ventricular hypertrophy, and sudden cardiac death. Media sclerosis and media calcification are not only driven by systemic factors such as hyperphosphatemia and hyperglycaemia, but are also critically dependent on vascular smooth muscle cells per se, which derive from multiple, non-overlapping embryonic origins that are reflected in different anatomical locations within the adult. Vascular smooth muscle cells are not terminally differentiated cells, and in this manner they can eventually react to stress or injury by transdifferentiating from contractile to proliferative and/or osteoblastic phenotypes. We postulate that the different developmental origins of vascular smooth muscle cells from the neuronal crest and the mesenchyma may lead to lineage-dependent identities and a heterogeneous susceptibility to develop media sclerosis and media calcification, where mesenchyma-derived arteries such as the abdominal aorta might be more prone to osteoblastic transdifferentiation and media calcification when compared to neuronal-crest derived arteries such as the thoracic aorta. We will test this hypothesis in different mice strains using histology, mass spectrometry, and vascular wire myography, respectively. Next, we will search for the molecular genetic determinants of lineage-specific phenotypic modulation of vascular smooth muscle cells and modulate their expression in primary cell culture experiments. In order to extrapolate our findings of the developmental basis of media calcification from mice to men, we will calculate the calcium scores of different arterial segments in patients with end-stage renal failure. Thereby, we will verify whether humans also show a mosaic pattern of media calcification with high calcium scores in arteries of mesenchymal origin, and low calcium scores in arteries of neuroectodermal origin. This study will ultimately provide us with promising targets for a rational pharmacotherapy to specifically modulate vascular smooth muscle cell behaviour, and thus strengthen the rationale for new therapeutic opportunities in the treatment of vascular disease, where media calcification is still associated with a heavy burden of morbidity and mortality in patients suffering from chronic renal failure and diabetes mellitus.

Arterial media calcification is still associated with a heavy burden of morbidity and mortality in patients suffering from chronic renal failure and diabetes mellitus. Therefore, we searched for new therapeutic concepts to treat and prevent these vascular changes that lead to arterial stiffness, left ventricular hypertrophy and sudden cardiac death. Arterial media sclerosis and media calcification are not only driven by systemic factors such as hyperphosphatemia and hyperglycaemia, but are also critically dependent on the micro-environment within the vessel wall. Thus, we analysed the molecular genetic determinants leading to different calcification patterns in different arteries. The abdominal aorta is more susceptible for vascular calcification when compared to the thoracic aorta, for instance. In these analyses, we found that autophagy is a natural protector from media calcification. Therefore, we pharmacologically induced autophagy in pre-clinical experiments and found that autophagy indeed resulted in less uremic media calcification and improved survival. These experiments provide the rationale to test pharmacological interventions that increase autophagy in patients suffering from chronic kidney disease. We also observed a conserved microRNA pattern in uremic media calcification. Importantly, down-regulation of microRNA-142-3p levels was significantly associated with increased arterial stiffness and impaired acetyl choline-mediated vascular relaxation of the aorta. Therefore, we pharmacologically restored the microRNA-142-3p bioavailability in pre-clinical tests and thereby improved the acetyl choline-mediated vascular relaxation and treated the arterial stiffness. These data underline the critical role of endothelium-derived factors that regulate the balance between vasoconstriction and vasodilatation. Taken together, this stand-alone project provided us with promising targets for a rational pharmacotherapy to specifically modulate vascular smooth muscle cell behaviour, and thus strengthen the rationale for new therapeutic opportunities in the treatment of vascular disease.