Endothelial NO Synthase Is Increased in Regenerating Endothelium After Denuding Injury of the Rat Aorta

Poppa, Veronica; Miyashiro, Jody K.; Corson, Marshall A.; Berk, Bradford C.

doi:10.1161/01.atv.18.8.1312

Cited by 50 publications

(37 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…It is of interest to note that these changes appear over the entire Regen including both injured and uninjured areas. Increased eNOS expression was reported 10 years ago by Berk and coworkers (34) in the Regen after rat carotid injury. The expression of eNOS is also increased in proliferating cultured endothelial cells (6).…”

Section: Discussionmentioning

confidence: 61%

Estradiol accelerates endothelial healing through the retrograde commitment of uninjured endothelium

Filipe¹,

Leen²,

Brouchet³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Although the accelerative effect of 17␤-estradiol (E2) on endothelial regrowth has been clearly demonstrated, the local cellular events accounting for this beneficial vascular action are still uncertain. In the present work, we compared the kinetics of endothelial healing of mouse carotid arteries after endovascular and perivascular injury. Both basal reendothelialization as well as the accelerative effect of E 2 were similar in the two models. Three days after endothelial denudation, a regenerative area was observed in both models, characterized by similar changes in gene expression after injury, visualized by en face confocal microscopy (EFCM). A precise definition of the injury limits was only possible with the perivascular model, since it causes a complete and lasting decellularization of the media. Using this model, we demonstrated that the migration of uninjured endothelial cells precedes proliferation (bromodeoxyuridine incorporation) and that these events occur at earlier time points with E2 treatment. We have also identified an uninjured retrograde zone as an intimate component of the endothelial regeneration process. Thus, in the perivascular model, the regenerative area can be subdivided into a retrograde zone and a reendothelialized area. Importantly, both areas are significantly enlarged by E2. In conclusion, the combination of the electric perivascular injury model and EFCM is well adapted to the visualization of the endothelial monolayer and to investigate cellular events involved in reendothelialization. This process is accelerated by E2 as a consequence of the retrograde commitment of an uninjured endothelial zone to migrate and proliferate, contributing to an enlargement of the regenerative area. endothelial regeneration; arterial injury; estrogen; carotid injury model; en face confocal microscopy THE INTEGRITY AND FUNCTIONALITY of the arterial endothelium, the very thin cell monolayer positioned at the interface between the blood and the vessel wall, play a crucial role in the physiology of circulation. Deendothelialization is the consequence of the treatment of coronary atherosclerosis disease by percutaneous transluminal coronary angioplasty, most often associated with intracoronary stents. One major drawback of this therapeutic approach is the residual in-stent restenosis, due to smooth muscle cell proliferation and intimal extracellular matrix accumulation. Drug-eluting stents releasing antimitotics (sirolimus and paclitaxel) efficiently prevent smooth muscle cell proliferation and, thereby, in-stent restenosis but increase the risk of late-stent thrombosis. This very serious event, commonly associated with sudden death or acute myocardial infarction, is at least partly the consequence of the inhibition of the reendothelialization of the stent struts by the antimitotics (13, 25).The endothelial healing after the injury process has previously and mostly been studied in larger animals. More than 20 years ago, a series of pioneer studies unraveled several cellular mechanisms involved in endot...

show abstract

Section: Discussionmentioning

confidence: 61%

Estradiol accelerates endothelial healing through the retrograde commitment of uninjured endothelium

Filipe¹,

Leen²,

Brouchet³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…NO has been considered as a double-edged sword. NO production is beneficial during several processes, including cell migration (30)(31)(32), but also may have other deleterious consequences, especially when produced at high concentrations, as has been reported in aneurysm rupture and atherosclerosis (33,34). NO generated at micromolar amounts arising from macrophages or smooth muscle cells, provoking extensive MMP-13 secretion, may contribute to the tissue remodeling associated with these conditions.…”

Section: Discussionmentioning

confidence: 97%

Matrix metalloproteinase 13 mediates nitric oxide activation of endothelial cell migration

López-Rivera

Lizarbe

Martínez‐Moreno

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

To explore the mechanisms by which NO elicits endothelial cell (EC) migration we used murine and bovine aortic ECs in an in vitro wound-healing model. We found that exogenous or endogenous NO stimulated EC migration. Moreover, migration was significantly delayed in ECs derived from endothelial NO synthase-deficient mice compared with WT murine aortic EC. To assess the contribution of matrix metalloproteinase (MMP)-13 to NO-mediated EC migration, we used RNA interference to silence MMP-13 expression in ECs. Migration was delayed in cells in which MMP-13 was silenced. In untreated cells MMP-13 was localized to caveolae, forming a complex with caveolin-1. Stimulation with NO disrupted this complex and significantly increased extracellular MMP-13 abundance, leading to collagen breakdown. Our findings show that MMP-13 is an important effector of NO-activated endothelial migration.angiogenesis ͉ endothelium ͉ vasular remodeling W ound healing is an orchestrated cascade of enzymatic activities that converge toward damage repair. Wound healing involves inflammation and angiogenesis and is tightly regulated by cytokines (1). Vascular endothelial growth factor (VEGF) is a critical cytokine involved in angiogenesis, and nitric oxide (NO) is a downstream effector (2, 3). VEGF increases NO levels in endothelial cells (ECs) by activating endothelial NO synthase (eNOS͞NOS3) (4-7). Recently, the role of eNOS in EC migration has been demonstrated in vivo and in vitro (8, 9) but the precise mechanism by which NO regulates migration is unknown.ECs migrate as a result of an injury and during angiogenesis from preexisting vessels. The process is tightly regulated by matrix turnover, in which matrix metalloproteinases (MMPs) play a pivotal role (10-12). We have previously reported that NO induces MMP-13 expression and activity in bovine aortic ECs (BAECs) (13,14).MMPs are extracellular matrix-degrading endopeptidases. MMP expression and activity can be found in physiological and pathological situations, such as tissue development, atherosclerosis, ovarian function, arthritis, osteoarthritis, cancer, angiogenesis, and wound healing (15). MMP-13 was initially discovered in mammalian cell carcinomas and is also expressed by several cell types, including endothelium (13,(16)(17)(18).Here, we present evidence that MMP-13 is a downstream effector of NO-activated EC movement. We have developed a wound-healing model in BAECs and aortic cells from eNOS WT and eNOS-deficient mice. We show that aortic ECs lacking MMP-13 experience delayed migration, and aortic ECs from eNOS null mice present delayed cell migration and a significant decrease in MMP-13 expression. In addition, we present data showing that MMP-13 exists in association with caveolin-1 in resting cells, and that this complex is disrupted in the presence of NO, leading to the secretion of MMP-13 to the extracellular media. We postulate that NO induces EC movement in part via the disruption of the MMP-13͞caveolin-1 complex, which in turn releases the secretion of active MMP-13 to the ...

show abstract

“…Although the role of eNOS in radiation-induced salivary gland injury remains unknown, it might be related to epithelial cell regeneration, since a marked increase in eNOS occurs in the denuded aorta and during the repair stage of inflammation (21,24).…”

Section: Measurement Of Omentioning

confidence: 99%

Peroxynitrite formation in radiation-induced salivary gland dysfunction in mice

et al. 2007

View full text Add to dashboard Cite

Xerostomia frequently arises in patients with head and neck malignancies that are treated by radiation. However, the mechanisms responsible for the destruction of the salivary gland remain unknown. We previously established a xerostomia model of mice and identified the pathway through which nitric oxide (NO) affects the pathogenesis of radiation-induced salivary gland dysfunction. Although the toxicity of NO alone is modest, NO with superoxide anion (O 2•− ) rapidly forms peroxynitrite (ONOO − ), a more powerful toxic oxidant. In this study, we used the experimental model to examine: 1) when NO and O 2•− production is maximum in the salivary gland after irradiation; 2) whether peroxynitrite, as assessed by nitrotyrosine production, is responsible for salivary gland dysfunction; and 3) the effect of the iNOS selective inhibitor, aminoguanidine (AG), on nitrotyrosine formation. The increases in production of NO and O 2•− in the salivary gland peaked on day 7 after irradiation. Nitrotyrosine detected immunohistochemically was significantly reduced by AG in the salivary gland. On the basis of these results, we concluded that NO together with O 2•− forms the more reactive ONOO − , which might be an important pathogenic factor in radiation-induced salivary gland dysfunction.Radiotherapy is an established therapy for head and neck malignancies, but the treatment field might include normal several tissues and organs. As a result, xerostomia due to salivary gland dysfunction is a clinically important side effect that is often irreversible (23, 25). The actions of radiation include a direct effect of the radiation itself and the indirect DNA injury caused by the •OH radical, which induces cell death and salivary gland atrophy (3, 17). However, the actual pathogenesis of radiation-induced xerostomia is obscure, and an effective treatment has not been established.We previously established a xerostomia model using mice and identified the inflammatory pathway through which NO affects the pathogenesis of radiation-induced salivary gland dysfunction (27). NO is a radical molecule and has been identified as a vascular endothelium-derived relaxing factor (7,9,20). NO is generated by three types of nitric oxide synthase (NOS): neural NOS, endothelial NOS and inducible NOS (20). The expression of inducible NOS (iNOS) is induced by inflammatory cytokines (1,19) and that large amounts of NO are continuously released from activated macrophages through the NADPH-dependent oxidant deamination of L-arginine (9). The toxicity of NO is due both to NO itself and to NO-derived reactive oxidants (4). The modest toxicity of NO is increased by rapidly binding with NO together with O 2•− to form ONOO − , which is a more powerful, toxic oxidant (25). However, most of these reactive oxidants can not be directly detected in vivo. Thus, nitrotyrosine is used as a biomark-

show abstract

Endothelial NO Synthase Is Increased in Regenerating Endothelium After Denuding Injury of the Rat Aorta

Cited by 50 publications

References 43 publications

Estradiol accelerates endothelial healing through the retrograde commitment of uninjured endothelium

Estradiol accelerates endothelial healing through the retrograde commitment of uninjured endothelium

Matrix metalloproteinase 13 mediates nitric oxide activation of endothelial cell migration

Peroxynitrite formation in radiation-induced salivary gland dysfunction in mice

Contact Info

Product

Resources

About