Role of Matrix Gla Protein and the Microcirculation in Differentiating Health from Disease

Matrix Gla protein (MGP) is a small protein (11 kD) synthesised by vascular smooth muscle cells and the endothelium. Activation of MGP requires two posttranslational modifications: vitamin K dependent γ‑glutamate carboxylation and serine phosphorylation. The objective of this dissertation was to disentangle the role of MGP and the microcirculation in differentiating health from disease. Population studies offer a unique opportunity to investigate the association of health outcomes analysed on a continuous or categorical scale with clinical characteristics, such as blood pressure, or biomarkers, such as MGP. With a focus on the retinal microvasculature, chronic kidney disease and diastolic left ventricular dysfunction, our research moved the state of the art forward by demonstrating that MGP not only inhibits macrovascular calcifications, as was already known before, but also plays a central role in maintaining the integrity of the microcirculation in the eye, kidney and heart. Moreover, we investigated whether the microcirculation might contribute to cognitive impairment in children born prematurely or to diastolic left ventricular dysfunction in response to risk factors, such as ageing or hypertension. Where possible, we underpinned our epidemiological findings in Flemish by replication in other cohorts or by conformation-specific staining of MGP moieties in renal or cardiac tissue samples.