Neural Crest‐Derived Valve Interstitial Cells Calcify In The Klotho‐Deficient Mouse Model Of Aortic Valve Disease

Abstract

Calcific aortic valve disease (CAVD) is characterized by calcification and stenosis of the valve. Cell lineage studies were performed to determine if the developmental origin of a valve interstitial cell (VIC) predetermines its calcific potential. Neural crest (NC)‐derived cells in the skull calcify during normal bone formation, therefore, it is hypothesized that NC‐derived VICs are primed to calcify in CAVD. In this study, klotho‐deficient (Kl‐/‐) mice were used as a model of CAVD as they develop robust aortic valve (AoV) calcification. Parallel lineage‐tracing experiments in wild type and Kl‐/‐ mice from crosses with Tie2‐Cre, Wnt1‐Cre, and Mef2cAHF‐Cre were performed to follow endothelial‐, NC‐, and second heart field (SHF)‐ derived VICs respectively. In normal AoVs, endothelial‐ and SHF‐ derived VICs contribute broadly to all leaflets, whereas NC‐derived VICs are found primarily in the right and left coronary leaflets and in the hinge region of all three leaflets. In the calcific lesions of Kl‐/‐ mice, there was a noted absence of endothelial‐derived VICs, which constitute the majority of the AoV. In contrast, NC‐derived VICs were abundant in calcific lesions in the hinge region of the leaflets. Thus, osteogenic potential may depend on the embryonic origin of the VICs. Understanding the capacity of VICs to calcify will elucidate the cellular mechanisms underlying CAVD. Funding is provided by NIH F32HL110390.