Inhibition of inducible nitric oxide synthase results in reductions in wound vascular endothelial growth factor expression, granulation tissue formation, and local perfusion

Howdieshell, Thomas R.; Webb, Whitney; Sathyanarayana,; McNeil, Patti L.

doi:10.1067/msy.2003.128

Cited by 35 publications

(24 citation statements)

References 31 publications

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“…It has been concluded that VEGF production in granulation tissue is dependent on the presence of functionally active i-NOS and hence, the production of NO. 15 On the other hand, very similar results with ours have been achieved by Shihab et al 16 In a rat model of chronic cyclosporine nephrotoxicity, VEGF expression is increased by NO blockade with l-NAME and decreased by NO enhancement with l-arginine. 16 In the present study, nonselective inhibition of NOS with l-NAME significantly decreased the free radical formation and NO production, and also significantly increased the VEGF level after spinal cord ischemia and reperfusion.…”

Section: Discussionsupporting

confidence: 86%

The correlation between nitric oxide and vascular endothelial growth factor in spinal cord injury

Savaş

Altuntaş

et al. 2007

Spinal Cord

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TurkeyStudy design: Prospective, randomized, placebo-controlled, experimental study. Objectives: The issue of whether nitric oxide (NO) production is beneficial or deleterious on ischemic injuries of the central nervous system still remains doubtful. Vascular endothelial growth factor (VEGF) is known to induce the release of NO from endothelial cells. However, the effect of NO on VEGF synthesis is not clear. We aimed to determine the effects of l-arginine and NG-nitro-l-arginine methyl ester (l-NAME) on VEGF synthesis and free radicals in a rat model of spinal cord ischemia-reperfusion (IR) injury. Setting: Surgical Research Laboratory of a Medical School. Material and methods: Twenty-eight Wistar rats were divided into four groups as follows (n ¼ 7): Sham, IR injury, l-arginine, and l-NAME. Infrarenal abdominal aorta was occluded to induce spinal cord ischemia. l-Arginine (100 mg/kg) and l-NAME (10 mg/kg) were given before aortic occlusion. Biochemical assays of malondialdehyde (MDA), NO and VEGF were carried out in spinal cord specimens. Results: l-Arginine treatment significantly increased MDA and NO, but decreased VEGF levels in spinal cord. However, nonselective inhibition of NOS with l-NAME significantly decreased MDA and NO, but increased VEGF levels. Besides, the positive linear correlation between MDA and NO, and negative linear correlations between MDA, NO and VEGF levels have also been demonstrated. Conclusion: Nonselective inhibition of NO synthase activity with l-NAME attenuated free radical formation and increased VEGF level when compared with NO precursor l-arginine in a rat model of spinal cord ischemia. We suggest that inhibition of NO synthase, as well as induction of VEGF, may be a therapeutic option in spinal cord IR injury.

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Section: Discussionsupporting

confidence: 86%

The correlation between nitric oxide and vascular endothelial growth factor in spinal cord injury

Savaş

Altuntaş

et al. 2007

Spinal Cord

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“…Experimental models of normal wound healing also demonstrate supernormal elevations of wound fluid NOx production during the course of healing. 18,34,36,45 Plasma NOx values remained constant during this observation period, whereas wound fluid NOx increased steadily after wounding. These studies established supernormal elevations of wound fluid NOx, produced primarily by wound macrophages after injury, as a constant feature that may be correlated with successful wound repair.…”

Section: Discussionmentioning

confidence: 88%

“…Reduced wound fluid NOx during impaired wound closure was, in turn, associated with decreased collagen accumulation, 34 wound tensile strength, type I and III collagen gene expression, 35 VEGF expression, granulation tissue formation, and wound microvascular perfusion. 36 Conversely, in studies of enhanced NO-mediated wound repair, increasing NOx measurements correlated with the successful reversal of impaired healing by interventional therapy with L-Arg supplementation 37 or adenoviral, inducible NO synthase (iNOS) replacement in iNOS knockout mice. 38 In the present study, HBOT was the intervention, and a progressive increase in wound fluid NOx occurred when HBOT was started; the increase was statistically significant at 1 and 4 weeks after HBOT.…”

Section: Discussionmentioning

confidence: 99%

Hyperbaric Oxygen Therapy Mediates Increased Nitric Oxide Production Associated With Wound Healing

Boykin

Baylis

2007

Advances in Skin &Amp; Wound Care

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Objective-The objective of this preliminary study was to document general somatic and wound nitric oxide (NO) levels during and after hyperbaric oxygen therapy (HBOT).Design-The study evaluated 6 chronic wound patients that responded favorably to HBOT treatment (20 treatments; 2.0 atmosphere absolute [ATA] × 90 minutes). Successful HBOT was associated with increased wound granulation tissue formation and significantly improved wound closure. Wound fluid and fasting plasma samples were obtained for measurement of nitrate and nitrite (NOx), the stable oxidation products of NO; plasma L-arginine (L-Arg); and asymmetric dimethylarginine (ADMA). NOx measurements were obtained before treatment (baseline), after 10 and 20 treatments, and at 1 and 4 weeks after therapy.Results-Wound fluid NOx levels tended to increase during treatments, were significantly elevated at 1 and 4 weeks after therapy, and correlated with reductions in wound area. Plasma L-Arg and ADMA were unchanged during and after HBOT.Conclusion-This preliminary study documents a significant increase in local wound NO levels (by NOx measurements) after successful HBOT and suggests that this mechanism may be an important factor in promoting enhanced wound healing and wound closure associated with this therapy.Hyperbaric oxygen therapy (HBOT) accelerates the healing of chronic wounds and is now primarily used as an adjunctive therapy in managing selected problem wound healing. [1][2][3][4] Hyperoxia during HBOT is an important mediating factor for wound collagen deposition and cross-linking, 5 neutrophil-dependent microbial killing, 6 and neovascularization. 7 Other HBOT-mediated processes in wound healing include the inhibition of integrin-mediated intravascular leukocyte adhesions and platelet aggregation, 8 enhancement of cutaneous microvascular homeostasis after ischemia-reperfusion syndrome, 9 increased oxygen capacitance and survival of ischemic flaps, 10 and upregulation of platelet-derived growth factor (PDGF) receptor mRNA. 11Experimental normobaric oxygen activates gene expression in human dermal fibroblasts, supporting the concept of oxygen as a possible signal transducer. 12 An additional signaling system modulated by oxygen availability is provided by the naturally occurring oxygen-free radicals (oxidants), or reactive oxygen species (ROS), found in the wound environment. ROS have been observed to increase cellular vascular endothelial growth factor (VEGF) expression and signal transduction that is considered to promote an overall enhancement of the wound healing process. 13 Further, accelerated wound healing during HBOT may be mediated by the combined effects of hyperoxia and the increased local (wound) production of nitric oxide (NO), an important cellular signal for tissue repair. 14,15 Ongoing experimental and clinical wound healing studies have established NO as a critical mediator of normal tissue repair. 16 Angiogenesis, granulation tissue formation, epidermal migration, collagen deposition, and microvascular homeostasis are signi...

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“…Although VEGF expression can be induced by a number of factors (including NO), hypoxia is the major inducer. 14,15 There is a clear association between angiogenesis and optimal wound healing, because the establishment of a new blood supply early on is vital to meeting the metabolic demands of the wound through each stage of the repair process. 10,16,17 The purpose of our study was to establish a model of systemic hypoxia to simulate the clinically relevant state of acute postoperative hypoxia.…”

mentioning

confidence: 99%

The Effects of Systemic Hypoxia on Colon Anastomotic Healing: An Animal Model

Attard

Raval

Martin

et al. 2005

Diseases of the Colon &Amp; Rectum

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This study validates a new animal model to study the effects of acute systemic hypoxia on colonic anastomotic healing. In this model, systemic hypoxia directly translated into local tissue hypoxia, and anastomotic healing was impaired. Contrary to our original hypothesis, hypoxia led to a significant increase in vascular endothelial growth factor and inducible nitric oxide synthase protein expression at the colonic anastomotic site. Impairment in anastomotic integrity despite upregulation of these angiogenic factors could be a result of the inability of wounded tissue to respond to vascular endothelial growth factor and inducible nitric oxide synthase or alternatively, hypoxia may adversely affect collagen synthesis and deposition directly.

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Inhibition of inducible nitric oxide synthase results in reductions in wound vascular endothelial growth factor expression, granulation tissue formation, and local perfusion

Cited by 35 publications

References 31 publications

The correlation between nitric oxide and vascular endothelial growth factor in spinal cord injury

The correlation between nitric oxide and vascular endothelial growth factor in spinal cord injury

Hyperbaric Oxygen Therapy Mediates Increased Nitric Oxide Production Associated With Wound Healing

The Effects of Systemic Hypoxia on Colon Anastomotic Healing: An Animal Model

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