This open access paper provides a perspective on some of the mechanisms of stiffening of blood vessels, though curiously without talking much about cross-linking of important structural molecules in the extracellular matrix. This stiffening is one of the most dangerous and damaging immediate consequences of the cell and tissue damage that lies at the root of aging. It causes hypertension, a condition of chronic high blood pressure, and a consequent detrimental remodeling of heart tissue. This leads to many of the varieties of cardiovascular disease, including an increased rate of breakage of tiny blood vessels in the brain, each destroying a tiny amount of tissue, but collectively causing a deterioration of cognitive function. Ultimately this results in vascular dementia, heart failure, and other fatal conditions. But it all starts with a loss of elasticity in blood vessels driven by mechanisms such as senescent cell accumulation, cross-link formation, and calcification in blood vessel walls.
Stiffening of the aorta and large elastic arteries is a hallmark of vascular aging. It has a number of adverse haemodynamic consequences, including a major contribution to isolated systolic hypertension. When measured by aortic pulse wave velocity (aPWV), it is highly predictive of clinical cardiovascular disease events independent of blood pressure, both in the general population and in groups with additional risk factors. Formerly thought to be simply a marker of atherosclerosis, the pathology of aortic stiffening may differ, at least in part, from that of atherosclerosis. Thus, in primate models of atherosclerosis, aPWV is reduced compared to non-atherosclerotic controls, at least in the early stages of atherosclerosis. In humans, aPWV is largely independent of risk factors other than age and blood pressure and is not elevated in the presence of non-calcified atheromatous plaque. The prognostic importance of arterial stiffening and the fact that it may be driven by a specific pathology distinct from atherosclerosis makes it an appealing target to prevent cardiovascular disease events.
In older subjects, calcification occurs in the media of the arterial wall around elastin fibres ('elastocalcinosis') and within atherosclerotic plaque in the intima. Although often regarded as distinct entities, intimal and medial calcifications often coexist. Arterial stiffening is closely associated with calcification, an association that could be explained by coexistent atherosclerosis. However, animal models show that medial calcification (in the absence of atherosclerosis) increases arterial stiffness, suggesting a direct causal relation between calcification and stiffening. Using combined computed tomography and magnetic resonance imaging to measure calcification and atheroma in the Twins UK population, we have shown that even though calcification often colocalises with atherosclerotic plaque, the association of stiffness with calcification is not explained by coexistent atheromatous plaque. Furthermore, the correlation between calcification and stiffness is explained by shared genetic factors distinct from those responsible for atherosclerosis. Arterial calcification is now known to be an active process resembling osteogenesis in which vascular smooth muscle cells undergo osteoblastic differentiation, expressing many of the proteins associated with bone formation and releasing vesicles into the extracellular matrix which serve as nucleation sites for the accumulation of hydroxyapatite crystals.
Whilst calcification may represent the later stages of a degenerative arteriosclerotic process that can be detected macroscopically, it is likely to be initiated by elastin degradation and a change in the type of collagen, which may also contribute to arterial stiffening independent of calcification. Such a degenerative process may relate to repetitive mechanical stress. It is thought to promote calcification through elastin-derived soluble peptides (matrikines or elastokines) which activate smooth muscle cell osteogenic differentiation and increase matrix affinity for nucleating mineral deposition. Matrix metalloproteinases (MMPs) degrade components of the extracellular matrix including elastin, and in vivo, MMP-mediated elastin degradation is closely associated with both medial calcification and increased arterial stiffness. MMPs are also implicated in cutaneous elastin degradation that may parallel changes in the arterial wall. MMP9 expression in the skin, for example, has been shown to relate to arterial stiffness.