@article {Weisenthal007112, author = {L. Weisenthal}, title = {Massively calcified endosomal death (MCED) of endothelial cells}, elocation-id = {007112}, year = {2014}, doi = {10.1101/007112}, publisher = {Cold Spring Harbor Laboratory}, abstract = {We have discovered a novel and specific mechanism of endothelial cell death. We refer to this novel death mechanism as massively calcified endosomal death, or MCED. Exposure of endothelial cells to non-specific toxins or other physical stresses induces death by traditional apoptotic and non-apoptotic mechanisms, common to most different types of cells. In contrast, exposure of endothelial cells (but not other types of nucleated cells) to specific insults, such as oxidized pathogenic lipids (e.g. 7-ketocholesterol) or agents with known anti-angiogenic activity (e.g. bevacizumab, certain tyrosine kinase inhibitors, etc.) triggers cell death via a novel pathway, which involves the formation of massively calcified endosomes, which, in turn, escape from the dying endothelial cells as massively calcified exosomes. These endosomes/exosomes appear capable of provoking an inflammatory response, characterized by physical association of calcified microparticles with inflammatory cells (monocytes, lymphocytes, neutrophils) with resulting increased release of an inflammatory mediator (TNF) into the culture medium. Traditional media for the culture of endothelial cells are profoundly inhibitory to MCED, as are some mammalian sera and many human sera, explaining why MCED had not been previously discovered and reported. The present discovery of MCED was accidental, resulting from work with primary cultures of fresh human tumor cell clusters, which invariably contain microcapillary cells. Our culture media are optimized for the tumor cells and not for the endothelial cells and, thus, are permissive of MCED. I propose MCED as the central mechanism underlying both intimal calcification and vascular inflammation in atherosclerosis.}, URL = {https://www.biorxiv.org/content/early/2014/07/15/007112}, eprint = {https://www.biorxiv.org/content/early/2014/07/15/007112.full.pdf}, journal = {bioRxiv} }