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Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase
Journal article   Open access   Peer reviewed

Aortic valve sclerosis in mice deficient in endothelial nitric oxide synthase

Ramzi N El Accaoui, Sarah T Gould, Georges P Hajj, Yi Chu, Melissa K Davis, Diane C Kraft, Donald D Lund, Robert M Brooks, Hardik Doshi, Kathy A Zimmerman, …
American journal of physiology. Heart and circulatory physiology, Vol.306(9), pp.H1302-H1313
05/01/2014
DOI: 10.1152/ajpheart.00392.2013
PMCID: PMC4010666
PMID: 24610917
url
https://doi.org/10.1152/ajpheart.00392.2013View
Published (Version of record) Open Access

Abstract

Risk factors for fibrocalcific aortic valve disease (FCAVD) are associated with systemic decreases in bioavailability of endothelium-derived nitric oxide (EDNO). In patients with bicuspid aortic valve (BAV), vascular expression of endothelial nitric oxide synthase (eNOS) is decreased, and eNOS −/− mice have increased prevalence of BAV. The goal of this study was to test the hypotheses that EDNO attenuates profibrotic actions of valve interstitial cells (VICs) in vitro and that EDNO deficiency accelerates development of FCAVD in vivo. As a result of the study, coculture of VICs with aortic valve endothelial cells (vlvECs) significantly decreased VIC activation, a critical early phase of FCAVD. Inhibition of VIC activation by vlvECs was attenuated by N G -nitro- l -arginine methyl ester or indomethacin. Coculture with vlvECs attenuated VIC expression of matrix metalloproteinase-9, which depended on stiffness of the culture matrix. Coculture with vlvECs preferentially inhibited collagen-3, compared with collagen-1, gene expression. BAV occurred in 30% of eNOS −/− mice. At age 6 mo, collagen was increased in both bicuspid and trileaflet eNOS −/− aortic valves, compared with wild-type valves. At 18 mo, total collagen was similar in eNOS −/− and wild-type mice, but collagen-3 was preferentially increased in eNOS −/− mice. Calcification and apoptosis were significantly increased in BAV of eNOS −/− mice at ages 6 and 18 mo. Remarkably, these histological changes were not accompanied by physiologically significant valve stenosis or regurgitation. In conclusion, coculture with vlvECs inhibits specific profibrotic VIC processes. In vivo, eNOS deficiency produces fibrosis in both trileaflet and BAVs but produces calcification only in BAVs.
 Vascular Biology and Microcirculation endothelial nitric oxide synthase aortic valve sclerosis bicuspid aortic valve

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