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Valvular Interstitial Cells Suppress Calcification of Valvular Endothelial Cells
Jesper Hjortnaes1, Kayle Shapero2, Josh Keegan3, Claudia Goettsch4, Jolanda Kluin1, John E. Mayer2, Joyce Bischoff5, Elena Aikawa4.
1University Medical Center Utrecht, Utrecht, Netherlands, 2Children's Hospital Boston/Harvard Medical School, Boston, MA, USA, 3Brigham and Women's Hospital, Boston, MA, USA, 4Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA, 5Children's Hospital Boston, Boston, MA, USA.

OBJECTIVE: Calcific aortic valve disease (CAVD) is the most common heart valve disease in the Western world. We previously proposed that valvular endothelial cells (VECs) replenish valve leaflets in response to injury via endothelial to mesenchymal transformation (EndoMT). In addition, it has been demonstrated that VECs could differentiate into osteoblastic cells. However, how this VEC plasticity interacts with valvular interstitial cells (VICs) with regards to valvular calcification is unknown. We hypothesized that aortic VECs can undergo osteogenic differentiation, but may be inhibited by VICs.

We used VEC clones that undergo TGFβ-mediated EndoMT,confirmed by significantly increased expression, compared to control, of EndoMT markers αSMA (5.3±1.2), MMP2 (13.5±0.6) and Slug (12±2.1) (p<0.05) [Fig. A, B]. We further investigated EndMT in the presence of VIC derived from the same valve leaflets as the VECs. Clonal populations of VICs were isolated and characterized, and shown to express an activated, myofibroblast-like phenotype. The VICswere placed in co-culture with VECs using a transwell system, in normal media and media supplemented with TGFβ. In the presence of VICs, TGFβ-mediated EndoMT in VECs was inhibited, as shown by decreased expression of αSMA (0.1±0.5), MMP2 (0.1±0.1) and Slug (0.2±0.2) (p<0.05). In addition, co-culture with VICs suppressed the migratory ability of TGFβ-stimulated VECs. When cultured alone in osteogenic media, VECs demonstrated osteogenic changes (Alizarin Red), confirmed by significant increases in mRNA expression of osteocalcin (8.6±1.3) and osteopontin (3.7±0.3), whereas the presence of VICs inhibited VEC osteogenesis shown by decreased expression of osteocalcin (0.4±0.1) and osteopontin (0.2±0.1) (p<0.05) [Fig. C, D]. Time course analysis revealed that EndoMT precedes osteogenesis, demonstrated by an initial increase of αSMA and MMP2 at day 7 followed by an increase of osteopontin and osteocalcin at day 14. .
CONCLUSIONS: This study shows that activated VICs inhibit EndMT and osteoblastic differentiation of VECs. EndoMT may precede the onset osteogenesis in VECs. These results indicate importance of VEC-VIC interactions in valve homeostasis and suggest a role for VECs in early CAVD..

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