The progressive stiffening of blood vessels is an important proximate cause of age-related hypertension and cardiovascular disease. One cause of this stiffening is a process of calcification, deposition of calcium into the tissues of blood vessel walls. Recent evidence shows that this process is caused by changes in cellular behavior, which opens up a range of potential targets for therapy and prevention. Here, researchers further demonstrate that the activities of senescent cells are probably involved in this picture. This is good news if validated, as targeted clearance of senescent cells as an approach to the treatment of aging is already heading towards the clinic, under active development at a number of companies.
Vascular calcification is an undervalued risk factor for the appearance of cardiovascular disease (CVD). Regarded as a surrogate marker for atherosclerosis, a condition that frequently precedes coronary events, calcification is commonly seen in the vasculature of elderly subjects, and in middle-aged subjects with premature vascular disease associated to chronic kidney disease. Hitherto, vascular calcification was thought to be a consequence of simple, physical mineral deposition in the vessel walls. New evidence, however, has revealed a highly regulated cellular response to be involved, and that calcification is the result of an imbalance between the inhibitors and inducers of calcium (Ca) deposition.
Microvesicles (MVs) - also named microparticles - are a subset of extracellular vesicles. Recent studies have shown that MVs produced by smooth muscle cells, can carry Ca as well as molecules that act as calcification nucleation sites. They may therefore also be involved in initiating vascular calcification. Endothelial senescence is known to be involved in the initiation of certain CVDs such as atherosclerosis and hypertension; the MVs produced by senescent endothelial cells (ECs) might therefore play an important role in their onset. Previous studies by our group have shown that microparticles produced by ECs in response to inflammatory stimuli, promote a calcifying response in vascular smooth muscle cells. The aim of the present study was to determine: 1) whether MVs produced by senescent, cultured ECs, plus those found in the plasma of elderly subjects, promote calcification in human aortic smooth muscle cells (HASMC), and 2) to determine which contents of such MVs might be involved.
The present results suggest that the MVs circulating in the plasma of elderly subjects contribute towards the calcification of vascular smooth muscle cells. In addition, those obtained for the in vitro-generated human umbilical vein endothelial cells (HUVEC) MVs strongly support the idea that calcification associated with aging is triggered by the MVs produced by senescent ECs. Certainly, the senescent HUVEC MVs contained increased amounts of Ca and bone-associated proteins. Compared to the younger subjects, the plasma of the elderly subjects contained a larger number of MVs in general, and of EC-produced MVs in particular. Only the MVs from the plasma of elderly subjects, and from senescent HUVEC, promoted the calcification of HASMC. It was very difficult to isolate sufficient bona fide EC-derived MVs from the plasma in order to confirm their having a role in vascular calcification. However, more than sufficient such MVs were isolated from senescent HUVEC.
The present results suggest that, with age, the number of MVs in the plasma increases, promoting vascular calcification. These MVs are likely produced by senescent ECs. Clinical studies are required to determine whether the number of calcifying MVs correlates with vascular calcification in elderly patients, and in those with premature vascular disease. The results also suggest that MVs could be used as markers of vascular calcification; their detection might be used to identify patients at risk of CVD and/or follow the clinical course of their disease. They also suggest that MVs might offer a therapeutic target for the control of vascular calcification and associated CVD.