Endothelial NO Synthase Overexpression Inhibits Lesion Formation in Mouse Model of Vascular Remodeling

Abstract

Abstract-NO produced by endothelial NO synthase (eNOS) plays important roles in the regulation of vascular tone and structure. The purpose of this study was to clarify the role of eNOS-derived NO on vascular remodeling by use of eNOS-transgenic (eNOS-Tg) mice. The common carotid artery was ligated just proximal to the carotid bifurcation. Four weeks later, the proximal carotid artery of the ligation site was histologically examined. In this vascular remodeling model, the endothelium remains uninjured, but neointimal and medial thickening occurs in combination with a reduction in vascular diameter at the proximal portion of the ligation. At 4 weeks after ligation, the respective neointimal and medial areas in wild-type mice were 17 200Ϯ1100 and 24 300Ϯ1500 m 2 , whereas both were reduced to 8000Ϯ1900 (PϽ0.01) and 18 400Ϯ700 m 2 (PϽ0.01) in eNOS-Tg mice (nϭ8). Total vascular area was not different between the 2 genotypes. N G -Nitro-L-arginine methyl ester treatment increased neointimal and medial areas to the same extent in both genotypes. Leukocyte infiltration was observed in the luminal side of the vessel, but the number of infiltrating cells was significantly attenuated in eNOS-Tg mice compared with wild-type mice. This reduction of leukocyte infiltration in eNOS-Tg mice was associated with reduced expressions of intracellular adhesion molecule-1 and vascular cellular adhesion molecule-1 on the endothelium. In conclusion, chronic eNOS overexpression in the endothelium reduced leukocyte infiltration and inhibited neointimal formation and medial thickening. Our data provide the evidence for the regulatory role of NO from the endothelium on vascular structure integrity. V ascular remodeling is an adaptive process that occurs in response to chronic changes in blood flow and other hemodynamic conditions, and a variety of vascular cellular responses, such as the growth and death of vascular smooth muscle cells and changes in extracellular matrix composition, are involved in the mechanisms. 1,2 Endothelial cells are thought to play a cardinal role in sensing changes in mechanical and biochemical forces and to regulate vascular structure. 3 One of the key molecules released by the endothelium is NO, synthesized by endothelial NO synthase (eNOS), which diffuses to underlying vascular smooth muscle cells or the lumen side and affects various cell functions. Over the past years, several studies have been performed involving the importance of endogenous eNOS-derived NO in vascular remodeling with the use of NO synthase (NOS) inhibitortreated animals and eNOS-deficient mice. 4 -6 Furthermore, eNOS gene transfer to the balloon-injured arteries in animal experiments has been shown to inhibit neointimal formation. 7-9 However, in those studies, eNOS was overexpressed mainly in vascular smooth muscle cells and/or the adventitia, not in the endothelium. On the other hand, no studies have ever tried to examine the effect of chronic overproduction of eNOS-derived NO from the endothelium on vascular remodeling. Recently, we gener...

Critical role of the NADPH oxidase subunit p47phox on vascular TLR expression and neointimal lesion formation in high-fat diet-induced obesity

“…Beginning at 22 weeks, mice common carotid artery lesions 17,18 were induced by ligation of the left common carotid artery. At 28 days after surgery, the experimental animals were euthanized to evaluate carotid artery neointimal formation.…”

“…Although our present studies demonstrated that carotid ligation induced a significant neointimal formation in DIO mice, we did not observe neointimal formation in control mice as other investigator reported. 17,18 Different mouse strain and genetic background have been shown to have a significant different in the neointimal formation in carotid ligation model. 45,46 Whether these factors contribute to this discrepancy in present studies remains unknown.…”

Nontranscriptional actions of the glucocorticoid receptor

“…NO produced by eNOS possesses anti-inflammatory, antiatherogenic, and anti-ischemic properties [71,72]. Enhanced NO production by administration of the eNOS substrate Larginine or upregulation of eNOS by statins confers stroke protection [73,74,75], and transgenic mice overexpressing eNOS show decreased leukocyte accumulation and reduced vascular lesion formation following vascular injury [76]. Conversely, mice with targeted disruption of eNOS (eNOS −/− ) exhibit increased vascular inflammation and larger cerebral infarctions following experimental ischemia [77,78], while inhibition of NOS activity decreases cerebral blood flow and increases infarct size after ischemia [79].…”

Multiple Kinase Involvement in the Regulation of Vascular Growth

“…VSMCs primarily regulate vascular tone and contraction and are important in the medial layer of arteries. In animal models of vascular injury, intimal and medial thickening is attributed to phenotypic switching of resident VSMCs and their proliferation and migration from the adventitia and media to the intimal space (Janssens et al, 1998;Kawashima et al, 2001;von der Thusen et al, 2004). Therefore, augmentation of neointimal formation in iatrogenic response to therapeutic intervention compromises flow and www.intechopen.com increases the risk of a cardiac event.…”

“…The molecular mechanisms of cGMP signaling are not well understood, since studies suggest that NO can both promote and inhibit pathological vascular remodeling (Kawashima et al, 2001;Ozaki et al, 2002;Rudic et al, 1998). Furthermore, recent studies provide sound evidence for NO-independent heme oxygenase (HO) and carbon monoxide (CO) as physiologically relevant signals capable of activating sGC and promoting cGMP signal transduction (Christodoulides et al, 1995;Siow et al, 1999;Tulis et al, 2001a;Tulis et al, 2001b;Tulis et al, 2005).…”