Valvular endothelial cells: Guardians or destroyers of aortic valve integrity?

Abstract

Atherosclerosis and calcific aortic valve disease (CAVD) are two distinct, morbid processes that share similar pathophysiological events. Both diseases are characterized by recruitment of immune cells, activation of inflammatory pathways, proliferation/differentiation of resident elements, remodeling of extracellular matrix and calcium deposition [ 1 Bentzon J.F. Otsuka F. Virmani R. Falk E. Mechanisms of plaque formation and rupture. Circ. Res. 2014; 114: 1852-1866 Crossref PubMed Scopus (1057) Google Scholar , 2 Yutzey K.E. et al. Calcific aortic valve disease: a consensus summary from the alliance of investigators on calcific aortic valve disease. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 2387-2393 Crossref PubMed Scopus (180) Google Scholar ]. However, while the actual impact of intimal calcification on plaque stability is still controversial [ [3] Otsuka F. Sakakura K. Yahagi K. Joner M. Virmani R. Has our understanding of calcification in human coronary atherosclerosis progressed?. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 724-736 Crossref PubMed Scopus (281) Google Scholar ], no uncertainty exists about the clinical harmful consequences of calcium deposition within the aortic valve. As a matter of fact, progressive stiffness of calcified leaflets leads to reduction of aortic valve area, which results in chronic left ventricular pressure overload. Clinical manifestations of the advanced disease are syncope, angina and inevitable progression towards end-stage heart failure. Aging is the major risk factor for CAVD and this explains way the disease prevalence is growing in the countries with the highest life expectancy (about 3% of Americans aged 75 and over are affected) [ [4] Mozaffarian D. et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation. 2015; 131: e29-322 Crossref PubMed Scopus (5504) Google Scholar ]. Nevertheless, several basic and clinical science studies performed in the last two decades clearly demonstrated that arterial and valve calcification should be considered as an active, finely regulated biological process, which is mainly characterized by the activation of osteogenic programs and/or the lost of anti-calcific defense mechanisms within the vascular/valve tissue [ 2 Yutzey K.E. et al. Calcific aortic valve disease: a consensus summary from the alliance of investigators on calcific aortic valve disease. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 2387-2393 Crossref PubMed Scopus (180) Google Scholar , 5 Demer L.L. Tintut Y. Inflammatory, metabolic, and genetic mechanisms of vascular calcification. Arterioscler. Thromb. Vasc. Biol. 2014; 34: 715-723 Crossref PubMed Scopus (240) Google Scholar ]. These new data are of great relevance since nowadays the only treatments available to cure CAVD consist of invasive therapeutic strategies (namely surgical or transcatheter aortic valve replacement) and there is a substantial need of new pharmacological targets. Valvular interstitial cells suppress calcification of valvular endothelial cellsAtherosclerosisVol. 242Issue 1PreviewCalcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. We previously proposed that valvular endothelial cells (VECs) replenish injured adult valve leaflets via endothelial-to-mesenchymal transformation (EndMT); however, whether EndMT contributes to valvular calcification is unknown. We hypothesized that aortic VECs undergo osteogenic differentiation via an EndMT process that can be inhibited by valvular interstitial cells (VICs). Full-Text PDF Open Access