Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival

Kane, Anthony J.; Barker, Jane E.; Mitchell, Geraldine M.; Theile, David E.; Romero, Rosalind; Messina, Aurora; Wagh, Milind; Fraulin, Frankie Og; Morrison, Wayne A.; Stewart, Alastair G.

doi:10.1038/sj.bjp.0703944

Cited by 66 publications

(50 citation statements)

References 32 publications

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“…Increased tissue survival resulting from iNOS-dependent enhancement of VEGF levels and an ensuing angiogenic response has been reported (23). These findings suggest that the SIS-ADSC grafts may contribute to tissue restoration by enhancing angiogenesis directly or indirectly.…”

Section: Discussionmentioning

confidence: 54%

Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction

Yang²,

Sikka

et al. 2012

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

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Porcine small intestinal submucosa (SIS) has been widely used in tunica albuginea (TA) reconstructive surgery. Adipose tissue-derived stem cells (ADSCs) can repair damaged tissue, augment cellular differentiation, and stimulate release of multiple growth factors. The aim of this rat study was to assess the feasibility of seeding ADSCs onto SIS grafts for TA reconstruction. Here, we demonstrate that seeding syngeneic ADSCs onto SIS grafts (SIS-ADSC) resulted in significant cavernosal tissue preservation and maintained erectile responses, similar to controls, in a rat model of bilateral incision of TA, compared with sham-operated animals and rats grafted with SIS graft (SIS) alone. In addition to increased TGF-β1 and FGF-2 expression levels, cross-sectional studies of the rat penis with SIS and SIS-ADSC revealed mild to moderate fibrosis and an increase of 30% and 40% in mean diameter in flaccid and erectile states, respectively. SIS grafting induced transcriptional up-regulation of iNOS and down-regulation of endothelial NOS, neuronal NOS, and VEGF, an effect that was restored by seeding ADCSs on the SIS graft. Taken together, these data show that rats undergoing TA incision with autologous SIS-ADSC grafts maintained better erectile function compared with animals grafted with SIS alone. This study suggests that SIS-ADSC grafting can be successfully used for TA reconstruction procedures and can restore erectile function.Peyronie's disease | incision and grafting procedures | penile surgery

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Section: Discussionmentioning

confidence: 54%

Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction

Yang²,

Sikka

et al. 2012

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

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“…11 The present study could explain this phenomenon because we now show that erythrophagocytosis, similar to platelet phagocytosis, 12 stimulates iNOS expression and because iron is known to promote lipid peroxidation 25 and ceroid formation. 8 The function of iNOS expression is not clear, but possible roles in atherogenesis and thrombus vascularization have to be considered because plaque progression 29 and angiogenesis during wound healing 30 are reduced in iNOS-deficient mice.…”

Section: Kockx Et Al Inos-expressing Macrophages and Microhemorrhagesmentioning

confidence: 99%

Phagocytosis and Macrophage Activation Associated With Hemorrhagic Microvessels in Human Atherosclerosis

Kockx

Cromheeke

Knaapen

et al. 2003

ATVB

200

135

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Objective-Previously, we demonstrated that activated inducible NO synthase (iNOS)-expressing foam cells in human carotid plaques often produce autofluorescent (per)oxidized lipids (ceroid Key Words: atherosclerosis Ⅲ microvessels Ⅲ inducible NO synthase Ⅲ hemorrhage Ⅲ erythrocytes I ntermittent growth is a characteristic of human atherosclerosis. This could be the consequence of recurrent rupture of the fibrous cap followed by thrombus organization into the plaque. 1,2 Other studies have suggested a causative role of hemorrhages of intraplaque microvessels in carotid plaque rupture. [3][4][5] Paterson et al 6 proposed the vascularization theory of plaque evolution by demonstrating hemosiderin deposition in early atheromatous plaques, and they related this to repeated intraplaque capillary rupture, but it remains unclear how hemorrhages contribute to lipid accumulation. Ceroid is one of these lipid components and consists of insoluble mixtures of oxidized lipids and proteins, which mark sites of previous oxidative events. 7 Macrophages play a central role in the production of this fluorescent pigment, and extracellular ceroid deposits ultimately accumulate in the necrotic core of the plaque. 7,8 Furthermore, the upregulation of inducible NO synthase (iNOS), a major ancillary pathway of host defense by activated macrophages, is a characteristic feature of foam cell-rich plaque regions. 9,10 Recently, we showed that iNOS, which is predominantly expressed in macrophages, 10,11 often colocalizes with ceroid 11 or platelet-derived amyloid ␤ 12 in advanced human plaques. Because the reasons See coverfor these associations are unclear, we investigated the role of microvessels in plaque progression. To this end, the distribution of microvessels, ceroid and iNOS (as a marker of macrophage activation), was systematically mapped in human carotid artery plaques. The expression of von Willebrand factor (vWf) in the endothelial cells of intraplaque microvessels is highly variable, ranging from undetectable to thick perivascular deposits. 5 The latter are due to increased vWf biosynthesis during atherogenesis. 13,14 Therefore, vWf was used as a marker of endothelial cell activation. For an unbiased identification of topographical associations, the results were subjected to a cluster analysis. Finally, the formation of iNOS-expressing ceroid-containing foam cells was demonstrated in normocholesterolemic settings on erythrophagocytosis by macrophages in experimental thrombi in rabbit carotid arteries and in murine J774 macrophages in culture. MethodsThe ethics committees of Middelheim Hospital and Antwerp University approved the studies.

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“…A second difference from previous experiments is that we used mice treated with iNOS inhibitor in the acute stage, as well as iNOS knockout mice, to examine the effect of iNOS [44]. It is noteworthy that one study in which iNOS knockout mice were used and reperfusion was not performed (similar to our protocol) found that injury was severe and angiogenesis in the chronic stage was augmented [45].…”

Section: Discussionmentioning

confidence: 99%

“…Many reports indicate that iNOS enhances angiogenesis in various neoplastic disease models [44,[47][48][49]. However, factors secreted by the cancer cells may play important roles in these models.…”

Section: Discussionmentioning

confidence: 99%

Biphasic Action of Inducible Nitric Oxide Synthase in a Hindlimb Ischemia Model

Kimura

Goto

Yagi

et al. 2006

J. Clin. Biochem. Nutr.

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Summary We investigated the influence of inducible nitric oxide synthase (iNOS) on acute ischemic injury and chronic angiogenesis. In a hindlimb ischemia model, NO produced by endothelial NO synthase (eNOS) reduces ischemic injury and promotes angiogenesis. However, the effect of the large amounts of NO generated by induced iNOS is unclear. Experimental groups of mice were as follows: (1) wild-type group (Wild), (2) iNOS-knockout group (iNOS-KO), and (3) aminoguanidine-treated wild-type group (Wild + AG), which received aminoguanidine from day 0 to day 3 after ischemia. Acute ischemic injury was evaluated by measuring the plasma CK value and ischemic score. Chronic angiogenesis was evaluated by microangiography and with a non-contact type Doppler blood flowmeter on day 3. Compared with the Wild group (251 ± 34.7 IU/l), the CK value was significantly elevated in the iNOS-KO (497 ± 126.7 IU/l) and Wild + AG (587.2 ± 128.7 IU/l) groups. The ischemic score was significantly increased in the iNOS-KO (92%) and Wild ± AG (66.6%) groups compared with the Wild group (23%). Blood flow was significantly increased in the iNOS-KO group (58.7 ± 15.3%) compared with the Wild (38.1 ± 15.9%) and Wild ± AG (43.5 ± 9.8%) groups in the chronic stage. Microangiography revealed a significantly increased number of blood vessels in the iNOS-KO (0.29 ± 0.02) group compared with the Wild (0.12 ± 0.01) and Wild + AG (0.15 ± 0.02) groups. Our findings indicate that NO generated by iNOS has a biphasic action, reducing acute ischemic injury and inhibiting angiogenesis in the chronic stage.

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Inducible nitric oxide synthase (iNOS) activity promotes ischaemic skin flap survival

Cited by 66 publications

References 32 publications

Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction

Adipose tissue-derived stem cell-seeded small intestinal submucosa for tunica albuginea grafting and reconstruction

Phagocytosis and Macrophage Activation Associated With Hemorrhagic Microvessels in Human Atherosclerosis

Biphasic Action of Inducible Nitric Oxide Synthase in a Hindlimb Ischemia Model

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