DISEASE FOCUS: Atherosclerosis and vascular calcification

Cellular Senescence and vascular calcification

.
Data suggesting that cellular senescence plays a role in vascular calcification was first presented by myself (as far as I am aware, please let me know otherwise) at the Integrative Physiology Post-Graduate Conference, Aberdeen (2007). The abstract was as follows:

A transcriptomic analysis of vascular smooth muscle cells

The senescence of mitotic cells is thought to play a role in ageing and age-related disease. To investigate this further, RNA was extracted from growing and senescent cultures of vascular smooth muscle cells (VSMCs) and subjected to microarray analysis. A literature search of genes involved in atherosclerosis and vascular calcification (an age-related vascular disease) was undertaken and the expression of those genes investigated using the microarray data of senescent VSMCs. Results show that genes known to be involved in atherosclerosis and vascular calcification are significantly up or down regulated in senescent VSMC. ELISA and Western blot analysis was used to validate the microarray data. These results suggest that senescent VSMCs play a role in the development and/or the progression of atherosclerosis and for the first time suggest a role in vascular calcification.

Data from this study (soon to be published) shows that those proteins which are either up or down-regulated at sites of calcification are also transcriptionally up or down-regulated in cultures of senescent vascular smooth muscle cells (VSMCs). The main two culprits involved in calcification appear to be matrix gla protein (MGP) and bone morphogenic proteins (BMP). MGP is normally expressed in endothelial cells and has been identified as a calcification inhibitor of the arterial wall and is thought to neutralise the known effects of BMPs (Zebboudj et al, 2002). In contrast, BMPs are important anabolic factors in bone formation and determinant of bone mineral content (Garrett et al, 2007).

In cultures of senescent VSMC, MGP expression is down-regulated 24-fold (the largest down-regulation of any gene on the chip (affymetrix)), whereas BMP2 is up-regulated more than 4-fold. Since control of BMP activity is important for normal bone formation, the up-regulation of BMPs in senescent VSMC (and the down-regulation of its inhibitor, MGP), suggests senescent VSMC play an important role in the pathophysiology of vascular calcification. BMP2 may be responsible for inducing osteoblastic differentiation of vascular smooth muscle cells, a process thought critical in the initiation of vascular calcification (Hruska et al 2005).

.

To further demonstrate the importance of MGP in preventing vascular calcification, MGP knock-out studies were carried out on mice (Luo et al, 1997). Mice lacking MGP died within a few months as a consequence of arterial calcification which lead to blood-vessel rupture. However, in calcified arteries, MGP expression has been found to be up-regulated (Mazzini and Schule, 2006), but this is probably an attempt (by non-senescent cells) to reduce the levels of calcification resulting from uncontrolled expression of BMP2.

.

In atherosclerosis, calcification can occur in advanced lesions. Stimulated proliferation of VSMC in developing plaques reduces the replicative capacity of those cells and increase the appearance of senescence cells. These senescent VSMC may up-regulate BMPs and down-regulate MGP, thus resulting in calcification.

Although, much more work is required to validate the microarray data and investigate these findings in living tissues, this preliminary work suggests for the first time that senescent VSMC may play a role in the development/progression of vascular calcification.

SEE: Burton et al (2009) Microarray analysis of senescent vascular smooth muscle cells: A link to atherosclerosis and vascular calcification