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Mechanisms of Vascular Remodeling in eNOS Knockout Mice
Author(s) -
Steed Mesia Moore,
Tyagi Neetu,
Rodriguez Walter,
Ovechkin Alexander,
Moshal Karni,
Tyagi Suresh C
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a711-c
Subject(s) - enos , medicine , knockout mouse , endocrinology , nitric oxide synthase type iii , matrix metalloproteinase , oxidative stress , nitric oxide , chemistry , endothelial dysfunction , reactive oxygen species , endothelium , zymography , nadph oxidase , nitric oxide synthase , biochemistry , receptor
Nitric oxide (NO) produced by endothelial nitric oxide synthase (eNOS) plays an important role in the regulation of vascular tone. It has been shown that mice deficient in eNOS have impaired endothelium, such as alterations in structure and function. However, the mechanism of this impairment is unclear. Previous studies have implicated reactive oxygen species (ROS) as playing an important role in the initiation and progression of endothelial damage. We hypothesize that a deficiency in endothelial derived NO initiates ROS production therefore promoting increased activation of matrix metalloproteinases (MMP) and subsequent vascular remodeling. The descending thoracic aorta of wild type (WT) and eNOS−/− mice were removed, cleaned, dissected and homogenates were prepared. Results: The assessment of aortic function by in vivo echocardiography showed an increase in wall thickness and decreased blood flow in the eNOS−/− aortas suggesting increased wall stiffness. Quantitative PCR analysis revealed a marked increase in NADPH oxidase (Nox‐4) and in contrast a decrease in thioredoxin (Trx) as well as an increase in MMP ‐2 and ‐9 in the knockout animal. Gelatin zymography showed a selective increase in MMP ‐9 activity in the eNOS−/− mice. Western blot analysis in eNOS−/− indicated a robust decrease in elastin expression. The stretch‐strain relationship of aortic rings was assessed in an isometric tissue myobath. WT aortas relaxed in response to 0.5g of tension while the eNOS−/− aortas remained constricted, indicating reduced vascular elastic compliance. These results show that eNOS deficiency leads to the degradation of vessel wall structural components initiated by oxidative stress and increased MMP activity that collectively result in aortic remodeling and eventual irregularities in the regulation of vascular tone.