δ-granules from thrombocytes and the origin of the early calcified structures of cardiovascular calcification

Abstract

Spherical calcium phosphate particles are calcified structures found at all stages of vascular calcification associated with diseases such as atherosclerosis, rheumatic fever, and aortic valve stenosis. These same particles are the first detectable calcified structures in vascular tissue. Their distinct physicochemical properties, compared to the larger calcific lesions observed later in disease progression, suggest a unique formation mechanism. Despite its clinical relevance, the origins and mechanisms of cardiovascular calcification remain strongly debated. In this study, we first evaluated the ubiquity and similarity of the spherical calcium phosphate particles in the vascular tissues of all vertebrate classes (fishes, amphibians, lizards, birds, and mammals). Our results revealed that identical calcified particles were present in all amniotic classes (mammals, birds, and reptiles), but absent in anamniotes (amphibians and fishes). This indicates a conserved mechanism of calcification among these vertebrates. Following the confirmation of their ubiquity, we used multiple methods to investigate the origin of these particles. Our findings suggest that they likely originate from δ-granules of thrombocytes (platelets in mammals), which gradually precipitate into spherical particles of calcium phosphate. Based on our results, we propose a novel mechanism for the formation of these particles, complementing existing models of cardiovascular calcification. This work introduces a previously unrecognised early event in the pathogenesis of cardiovascular calcification, offering new insights into disease progression and potential therapeutic targets.