Are our blood vessels slowly turning to bone?
Are our blood vessels slowly turning to bone?
Vascular calcification occurs when calcium phosphate minerals accumulate in the blood vessels, myocardium and cardiac valves.(Giachelli, 2004) The calcium phosphate minerals are not only deposited via physicochemical mechanisms in the vasculature, the vasculature itself has also been found to play a role in ossification of the vessels.(Demer and Tintut, 2008) For many years it was thought that these accumulations of calcium deposits were only of importance when associated with calcification of the heart valves however new research indicates that these deposits in the blood vessels should not be ignored. Myocardial infarctions and CVD may be directly caused or exacerbated by vascular calcification. Cardiovascular disease has recently been closely linked to the degree of calcification of the blood vessels especially in coronary arteries.(Proudfoot et al., 2000)
There are two main types of vascular calcification which are recognized. The first is Intimal calcification which refers to calcification caused by an atherosclerotic lesion which damages the blood vessel. Atherosclerosis is a deposition of lipids, cholesterol and calcium which narrow the lumen of the artery and reduce blood flow. This process on its own is a large cause for concern in the western hemisphere and it is a major cause of mortality.(Proudfoot et al., 2000) The calcification of the atherosclerotic lesion only intensifies the problem as the blood vessel is occluded. The second type is called Mönckeberg's sclerosis which occurs in the media of the artery and is caused by dismetabolic syndrome, age, diabetes and is fairly common in chronic kidney disease cases.(Giachelli, 2004) This process reduces the elasticity and increases the rigidity of the blood vessel. With a large prevalence of vascular calcification in the elderly population there is no doubt as to whether it exists as a process however, to decide whether our blood vessels are slowly turning to bone I will be assessing the importance of several interconnected mechanisms which may contribute to calcification.(Demer and Tintut, 2008)
The process of vascular calcification draws many parallels with embryonic bone formation and causes the vascular smooth muscle cells to lose their compliance and elasticity.(Demer and Tintut, 2008) The aorta and other major arteries store energy during the systole phase of cardiac muscle contraction, they then release this energy in diastole to reduce the work done by cardiac muscle. When calcification of the aorta occurs this energy is no longer stored during systole and therefore the cardiac muscle has to work harder during diastole. To understand whether our blood vessels are turning to bone or whether they are simply losing their elasticity due to calcium deposits, a comparison between vascular and skeletal calcification is necessary. Both vascular calcifications and bone have traces of magnesium and carbonate within their structure. Vertebrates as a whole have evolved in an environment with a high concentration of calcium and have therefore needed mechanisms to inhibit the mineralization of soft tissues, these mechanisms of inhibition would prevent the formation of bone if it was not for certain overriding mechanisms. For example the molecule pyrophosphate is an inhibitor of bone formation (calcification). Matrix vesicles which attach to the cell membrane of cells to be mineralized contain a high density of alkaline phosphatase which breaks down the pyrophosphate allowing calcification to occur uninhibited. This inhibition and overriding mechanism is the same in bone and vascular smooth muscle cells. A balance between inhibition and promotion of osteogenesis is the key to understanding how calcification occurs.(Demer and Tintut, 2008)
There are miscellaneous factors that appear to contribute to vascular calcification. End stage renal disease and chronic renal disease stage 5 appear to have a significant impact on the rate of calcification.(Lu et al., 2007) These two diseases impact on the modifiable (inhibibition) and unmodifiable (age, diabetes) factors involved. Patients on dialysis who have Chronic kidney diseases have been found to have an increased prevalence of vascular calcification than the general population and are more at risk of cardiovascular disease as a result of this.(Cannata-Andia et al., 2006) Also an increased number of bone fractures in the body correlates to an increase in vascular calcification. Several more integrated biological systems contribute to the deposition of bioapatite in the cardiovascular system. These systems are thought to interact together and are not mutually exclusive. I will discuss the mechanisms of each system and then decide on the importance attributed to each.(Giachelli, 2004)
Calcium and phosphate blood plasma levels although a seemingly simple factor play a complex role in calcification as an elevated level of these two minerals will potentially aggravate any of the causes I will discuss below. In cell cultures vascular smooth muscle cells are able to create mineralized formations of bone but a phosphorus supply must be available, therefore calcium must be in the presence of phosphorus to initiate calcification.(Giachelli, 2004)
Evidence has been found in several clinical studies that high levels of calcium and phosphate (hyperphosphataemia and hypercalcemia) lead to an increased expression of osteogenic factors within vascular smooth muscle cells. These osteogenic factors are termed BMP's, the member of the bmp family that has the most extensive research history is BMP2, this protein is thought to have a large impact on bone mineralization in vessels by potentiating the effects of MSX-2 which is a transcription factor essential for the formation of bone.(Hruska et al., 2005) Precursors such as osteopontin and osteocalcin have been found in sites of atherosclerosis know as atherosclerotic plaques. Although these proteins are involved mainly in bone formation their presence at these sites of atherosclerosis indicate that they also perform similar processes in the vascular system. These bone morphogenic proteins are expressed almost identically to those found in bone however they are able to mineralize tissues in the extracellular matrix of vascular tissue.(Wada et al., 1999)
Clinical trials have shown that blood vessels contain genes which code for inhibitors of biomineralization, if these genes are not expressed or translated an increased amount of calcium phosphate is deposited. A lack of matrix gla protein, osteoprotegerin and pyrophosphate have been correlated to an immediate increase in vascular calcification even when no atherosclerosis is present. (Schinke and Karsenty, 2000). Osteoprotegerin inhibits osteoclastogenesis by preventing the activation of the Rank receptor which is necessary for the formation of bone. Osteoprotegerin stops the rank receptor from being activated by binding to Rankl.(Bezerra et al., 2005) Matrix GLA protein is found primarily in the bone matrix, this may appear to suggest that it is a bone morphogenic protein however this is not the case. In aortic smooth muscle cells it was found that an increase in extracellular calcium concentration led to the increased translation of the Matrix GLA suggesting that this protein plays a major role in regulating the mineralization of tissues. Research suggests that matrix GLA works by inhibiting mesenchymal cell differentiation in bone. It is also thought to inhibit the action of BMP-2 which I have previously discussed. A lack of matrix GLA protein alone in does not result in massive calcification of the arteries, only the cartilage is affected. This indicates that other inhibiting proteins are present and that inhibition is a dynamic process.(Abedin et al., 2004) There are also inhibitors of vascular calcification which do not arise from the blood vessels such as fetuin which disrupts the formation of apatite and consequently lowers the risk of cardiovascular disease. (Giachelli, 2004)
The inhibitors present themselves in blood vessels in varying levels based on age and genetics, the large majority of sufferers of vascular calcification are above the age of 60 suggesting a possible decrease in gene transcription or translation although mechanisms are still unclear. The fact that these inhibitors are present in the vasculature has forced physicians to rethink their position on the Ca x P product quotient. This value was formerly used to assess whether a patients level of calcium and phosphorus were safe regarding calcification however if an individual has a reduced expression of inhibitors their value must be lowered accordingly.(Adragao et al., 2004)
When bone is reformed or repaired after a fracture or damage due to osteoporosis there are two main cells involved. Osteoclasts and osteoblasts, the osteoclasts which are large multinucleated cells break down the matrix of the bone and this is termed resorption, the osteoblasts on the other hand form bone, when this process occurs circulating nucleational complexes are released from these sites of bone formation and these complexes are involved in vascular calcification.(Bezerra et al., 2005, Giachelli, 2004) This fact has helped to elucidate the high incidence of vascular calcification in postmenopausal women who suffer from osteoporosis. The apoptotic death of cells refers to the programmed death of cells, this process occurs so as not to damage the host organism. Apoptosis provides a large amount of free membrane phospholipids so that new matrix vesicles can be formed. (Proudfoot et al., 2000) There is evidence that these apoptic bodies bear a very close biochemical resemblance to the matrix vesicles that are found in calcified vascular smooth muscle cells.(Hashimoto et al., 1998) Matrix vesicles have been a breakthrough in our understanding of how vascular calcification occurs. They are thought to mineralize cartilage and bone. Electron microscopy has established these vesicles in calcified arteries and in vitro tests have shown that the inhibition of cell apoptosis also reduces the extent of the calcification.(Yadon et al., 2000)