Role of valve endothelial cells and extracellular vesicles in aortic valve calcification in vitro

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Abstract Aortic valve calcification is mediated by valve interstitial cells (VICs). We hypothesized that valve endothelial cells (VECs) stimulate pro-osteogenic changes in VICs, potentially via extracellular vesicles (EVs). We investigated VECs' pro-osteogenic effects on VICs, compared proteomes of healthy versus calcified VECs, and examined VECs-derived EVs effects on calcification. Human VECs and VICs were co-cultured in 2D and 3D (collagen gel) formats with osteogenic induction. Proteomic analysis compared VECs from healthy and calcified valves. Pro-osteogenic markers were assessed by qPCR, gel contractility was measured, and VECs-derived EVs were added to VICs cultures. In 2D co-cultures, induced calcification almost doubled versus VICs monocultures (p = 0.008). In 3D co-cultures, VECs from calcified valves induced strongest pro-osteogenic marker transcription in healthy VICs and reduced gel contraction. Proteomic analysis identified 3378 proteins with 27 and 8 proteins exclusive to healthy or calcified VECs, respectively. Nitric oxide synthase 3 and Hedgehog-interacting protein increased in calcified VECs (p = 0.005 and 0.002). VECs-derived EVs did not influence VICs calcification. VECs from calcified valves possess enhanced pro-osteogenic properties and promote VICs calcification independently of EVs. Pro-calcification EVs likely originate from other valve cell types.

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