© 2000 American Heart Association, Inc.
Integrative Physiology |
Temporal Events Underlying Arterial Remodeling After Chronic Flow Reduction in Mice
Correlation of Structural Changes With a Deficit in Basal Nitric Oxide Synthesis
From the Department of Pharmacology (R.D.R., M.B., D.F., W.C.S.), Yale University School of Medicine and Boyer Center for Molecular Medicine, and The John B. Pierce Laboratory and Department of Cellular and Molecular Physiology (S.S.S.), Yale University School of Medicine, New Haven, Conn.
Correspondence to William C. Sessa, PhD, Boyer Center for Molecular Medicine, Room 436D, Yale University School of Medicine, 295 Congress Ave, New Haven, CT 06536. E-mail william.sessa{at}yale.edu
Abstract—To define the cellular
events of vascular remodeling in mice, we measured blood flow and
analyzed the morphology of remodeled vessels at defined points
after a flow-reducing remodeling stimulus for 3, 7, 14, and 35 days.
Acute ligation of the left external carotid artery reduced blood flow
in the left common carotid artery (LC) compared with sham and
contralateral right common carotid arteries (RCs). In
morphometric analyses, the decrease in diameter in LCs was
reversible by vasodilator perfusion 3 days after ligation, whereas
ligation for 7 days or greater resulted in a permanent diameter
reduction. Coincident with structural remodeling at day 7 was an
increase in cell death in remodeled LCs. Functionally, rings from
remodeled LCs contracted to prostaglandin
F2
and relaxed to acetylcholine in a manner
identical to that of control arteries. However, remodeled LCs were
hypersensitive to the nitrovasodilator sodium nitroprusside (at day 7)
and exhibited a marked reduction in basal NO synthesis at 7 and 14 days
after ligation. The impairment of endothelial NO
synthase function was likely due to post-translational mechanisms,
given that endothelial NO synthase mRNA and protein
levels did not change in remodeled LCs. These data define the ontogeny
of flow-triggered luminal remodeling in adult mice and suggest that
endothelial dysfunction occurs during reorganization of
the vessel wall.
Key Words: vascular • apoptosis • ß-actin • endothelial NO synthase • endothelium
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