Redox signaling in vascular calcification - Dual role of NOX proteins

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Cardiovascular (CV) calcification, which is defined as pathological calcific mineral deposition within heart valves and arteries, has emerged as a predictor of and contributor to cardiovascular morbidity and mortality. However, the molecular mechanisms for the accelerated calcification are poorly understood. Evidence suggests that coronary artery calcification, particularly when present as microcalcification, reduces plaque integrity and triggers rupture and subsequent acute myocardial infarction, a global health threat and socio-economic burden. Recently, we made the novel observation that calcifying extracellular vesicles released by vascular smooth muscle cells are the smallest nidus to form microcalcification. On a molecular level, we showed that post-translational modification of the lysosomal sorting receptor sortilin, regulates the calcification propensity of these extracellular vesicles. By better understanding the biogenesis and downstream functional consequences of calcifying extracellular vesicles we will gain novel insights into the pathogenesis of vascular calcification. The scientific purpose of this research proposal is to examine the cellular and molecular mechanism and machinery that facilitates the nidus for vascular calcification and is based on the hypothesis that specific extracellular vesicles make essential contributions to the initiation of vascular calcification. We aim to understand (I) the specific molecular machinery that functionally regulates the unique cargo loading of calcification-prone biomolecules into extracellular vesicles and (II) the consequence of these calcification-prone extracellular vesicles on intercellular communication.We hypothesize that changes in redox signaling alter organelle rearrangements causing favored loading of calcification-prone biomolecules into EVs thus accelerating vascular calcification via macrophage activation. We aim to investigate A) the role of NOX-mediated redox signaling in the progression of vascular calcification and the calcification potential of extracellular vesicles, and B) the contribution of organelle rearrangement in particular endoplasmic reticulum-mitochondria interface. Furthermore, we aim to examine C) the impact of calcifying extracellular vesicles on intercellular communication within the atherosclerotic plaque. We will utilize established in vitro and in vivo calcification models in combination with loss-of and gain-of function experiments as well as molecular imaging and high resolution microscopy. This research program might exploit to generate novel therapeutic and diagnostic strategies to control pathophysiological calcific response that is of high unmet clinical need especially in the high-risk population of chronic kidney disease patients.