Calcific aortic stenosis and atherosclerosis share many similar characteristics suggesting that similar mediators and pathogenic pathways are involved. In both conditions, the native cells are quiescent. However upon damage, both valve interstitial cells (VICs) and smooth muscle cells (SMCs) in the valve and the vascular wall respectively undergo remodelling and transformation. We hypothesise that the smooth muscle cell phenotype plays a role during the calcification process. 12 normal and 16 calcified valves were analysed for smooth muscle markers including smooth muscle α-actin, smooth muscle myosin, calponin, caldesmon, desmin, SM1 and SM2 by immunocytochemistry. The expression of myocardin-related transcription factors, (MRTFA/B) as key regulators of smooth muscle gene expression, was also evaluated. Normal human valves demonstrated the expression of smooth muscle markers localised to the base of the valve. Occasionally smooth muscle markers were seen in small groups of cells in the region from the base to the central region of the valve but never in the region from the central to the co-apting edge. Smooth muscle markers in all the calcified valves demonstrated an increased and aberrant expression. The expression of smooth muscle myosin, SM1, SM2, calponin and smooth muscle α-actin was found to be abundantly expressed around calcified nodules and distal to the nodules. The pattern of staining was frequently localised along the majority of the valve tissue as well as in isolated cells. Additionally, regions of the endothelium and endothelial cells lining the vessels were found to be positive for smooth muscle markers in 9/16 calcified valves. Normal valves did not demonstrate any expression of MRTFs. However, MRTF-A and MRTF-B were induced in calcified valves in a similar pattern to the expression of smooth muscle markers. They were also induced in the endothelium and the endothelial cells lining some vessels. Importantly, the expression of MRTFs was nuclear in both VICs and endothelial cells indicative of activation. TGFβ1 (10ng/ml) was able to induce and translocate the expression of MRTF-A to the nucleus in VICs within 4 hours in some isolates. Calcified valves harbour a greatly increased number of smooth muscle marker-positive VICs and endothelial cells. This aberrant expression in endothelial cells may emulate endothelial to mesenchymal transformation (EMT) during embyonic valvulogenesis. Concomittantly, calcified valves expressed MRTFs, key regulators of smooth muscle gene expression. The presence of smooth muscle cell markers and MRTFs in calcified valves suggest a role for this cell phenotype in the development of the calcification process.


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  • Accepted: 28 May 2012
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