The significance of programmed cell death or apoptosis and matrix vesicles in atherogenesis.

Programmed cell death or its current synonym, apoptosis, is considered a genetically controlled biological process of cell deletion complementary to cell replication. Apoptosis is most likely a self-regulatory mechanism whereby a genetically determined biochemical pathway to death is initiated in cells sustaining irreparable damage particularly of DNA. Initiating factors in each instance need to be established. Identified in arteries, apoptosis correlates with the localization and severity of atherosclerosis. Granulovesicular disintegration of vascular smooth muscle cells leads to abundant vesicular debris mostly in the intima and increasing with age and hypertension and such matrix vesicle production is a major pathogenetic feature of atherosclerosis. The abundant debris produced accumulates lipid and minerals as usually occurs in non-phagocytosed cell debris. Similar vesiculation in erythrocytes under haemodynamic stress supports the contention that vascular cells under haemodynamic biomechanical stresses in spontaneous and experimental atherosclerosis degenerate due to depletion of cytoplasm, DNA fragmentation and oxidative damage with some cells inevitably undergoing terminal apoptosis. Evaluation of apoptosis must take into account the concomitant changes in the whole vessel wall and its matrix. Currently generalizations about therapeutic or pathogenetic roles for apoptosis in any disease are speculative and unwarranted.

X-ray microanalysis of mineralized matrix vesicles of experimental saccular aneurysms.

An energy dispersive X-ray microanalytical study was designed to examine the mineral deposits in matrix vesicles found in the walls of experimental aneurysms from two rabbits (103 and 1071 days postoperatively) and two sheep aneurysms (234 and 1202 days postoperatively). The freeze-substitution technique was adopted for use to retain inorganic ions in situ. Numerous, various sized extracellular electron-dense structures, believed to be matrix vesicles were observed. Size histograms for the mineralized vesicles showed that the proportion of smaller vesicles was higher in the older animals. A total of 370 vesicles were analyzed. Calcium and phosphorus with small amounts of magnesium were identified. No particular calcium phosphate mineral was dominant with the mean Ca/P molar ratio for all animals falling in the 1.1-1.2 range. Correlation coefficients for interrelationships between calcium, phosphorus, magnesium, and size were weak except for calcium vs phosphorus which was close to one, consistent with some type of calcium phosphate being the major constituent of the mineralized vesicles. Smaller electron-dense particles, probably mitochondrial granules were seen in some smooth muscle cells; a small number were analyzed and contained calcium and phosphorus (mean Ca/P molar ratio of 0.86) but no magnesium.