Nitric Oxide-Dependent Neovascularization Role in the Lower Extremity Disease

Mendoza, Mónica; Robles, Hilda Vargas; Romo, Eunice; Rı́os, Amelia; Escalante, Bruno

doi:10.2174/138161207782794103

Cited by 19 publications

(14 citation statements)

References 48 publications

(68 reference statements)

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“…Bearing on this conclusion, previous reports documented that 20-HETE has pro-angiogenic activity in vitro [10–16,21,22] and promotes corneal neovascularization [16] and skeletal muscle angiogenesis [15] in vivo . Interestingly, 20-HETE has been shown to have both assenting and opposing actions on nitric oxide (NO), an important regulator of ischemia-induced angiogenesis [40], in different vascular beds [39,41]. Therefore, potential interactions between increased 20-HETE and NO within the context of ischemia-induced angiogenesis remain to be studied.…”

Section: Discussionmentioning

confidence: 99%

20-HETE contributes to ischemia-induced angiogenesis

Chen

Joseph

Zhang

et al. 2016

Vascular Pharmacology

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Angiogenesis is an important adaptation for recovery from peripheral ischemia. Here, we determined whether 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia-induced angiogenesis and assessed its underlying molecular and cellular mechanisms using a mouse hindlimb-ischemia angiogenesis model. Hindlimb blood flow was measured by laser doppler perfusion imaging and microvessel density was determined by CD31 and Tomato Lectin staining. We found that systemic and local administration of a 20-HETE synthesis inhibitor, DDMS, or a 20-HETE antagonist, 6,15-20-HEDGE significantly reduced blood flow recovery and microvessel formation in response to ischemia. 20-HETE production, measured by LC/MS/MS, was markedly increased in ischemic muscles (91 ± 11 vs 8 ± 2 pg/mg in controls), which was associated with prominent upregulation of the 20-HETE synthase, CYP4A12. Immunofluorescence co-localized increased CYP4A12 expression in response to ischemia to CD31-positive EC in the ischemic hindlimb microvessels. We further showed that ischemia increased HIF-1α, VEGF, and VEGFR2 expression in gracilis muscles and that these increases were negated by DDMS and 6, 15-20-HEDGE. Lastly, we showed that ERK1/2 of MAPK is a component of 20-HETE regulated ischemic angiogenesis. Taken together, these data indicate that 20-HETE is a critical contributor of ischemia-induced angiogenesis in vivo.

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Section: Discussionmentioning

confidence: 99%

20-HETE contributes to ischemia-induced angiogenesis

Chen

Joseph

Zhang

et al. 2016

Vascular Pharmacology

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“…Also, NO is supposed to be one of the signaling molecules induced by Ach [ 13 ]. NO has actions on revascularization of the ischemic limb: increased NO levels were found in the ischemic limb, the lack of NO impairs the process of revascularization, and the improvement of NO levels improves revascularization [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

Treatment with Sildenafil and Donepezil Improves Angiogenesis in Experimentally Induced Critical Limb Ischemia

Constantinescu

Bolfă

Mironiuc

et al. 2017

BioMed Research International

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Objectives. In this study, we aimed to demonstrate the role of sildenafil (an antagonist of phosphodiesterase type 5 (PDE-5)) and donepezil (a specific and reversible inhibitor of acetylcholinesterase (Ach)) in increasing ischemia-induced angiogenesis. Method. Critical limb ischemia was induced by ligation of the common femoral artery followed by ligation of the common iliac artery. The operated animals were divided into 3 groups: receiving sildenafil, receiving donepezil, and surgery alone; the contralateral lower limb was used as a negative control. The results were controlled based on clinical score and Doppler ultrasound. Gastrocnemius muscle samples were taken from all animals, both from the ischemic and nonischemic limb and were used for histopathological and immunohistochemical examination for the evaluation of the number of nuclei/field, endothelial cells (CD31), dividing cells (Ki-67), and vascular endothelial growth factor (VEGFR-3). Results. An increasing tendency of the number of nuclei/field with time was observed both in the case of sildenafil and donepezil treatment. The formation of new capillaries (the angiogenesis process) was more strongly influenced by donepezil treatment compared to sildenafil or no treatment. This treatment significantly influenced the capillary/fiber ratio, which was increased compared to untreated ligated animals. Sildenafil treatment led to a gradual increase in the number of dividing cells, which was significantly compared to the negative control group and compared to the ligation control group. The same effect (increase in the number of Ki-67 positive cells) was more obvious in the case of donepezil treatment. Conclusion. Donepezil treatment has a better effect in ligation-induced ischemia compared to sildenafil, promoting angiogenesis in the first place, and also arteriogenesis.

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“…Ischemic injury in normal tissue is characterized by a revascularization compensatory response including angiogenesis and arteriogenesis, but this response is defective in CLI [ 6 ]. This may result in extensive muscle necrosis [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Muscle Derived Stem Cells Stimulate Muscle Myofiber Repair and Counteract Fat Infiltration in a Diabetic Mouse Model of Critical Limb Ischemia

Tsao

Kovanecz

Awadalla

et al. 2016

J Stem Cell Res Ther

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Background Critical Limb Ischemia (CLI) affects patients with Type 2 Diabetes (T2D) and obesity, with high risk of amputation and post-surgical mortality, and no effective medical treatment. Stem cell therapy, mainly with bone marrow mesenchymal, adipose derived, endothelial, hematopoietic, and umbilical cord stem cells, is promising in CLI mouse and rat models and is in clinical trials. Their general focus is on angiogenic repair, with no reports on the alleviation of necrosis, lipofibrosis, and myofiber regeneration in the ischemic muscle, or the use of Muscle Derived Stem Cells (MDSC) alone or in combination with pharmacological adjuvants, in the context of CLI in T2D. Methods Using a T2D mouse model of CLI induced by severe unilateral femoral artery ligation, we tested: a) the repair efficacy of MDSC implanted into the ischemic muscle and the effects of concurrent intraperitoneal administration of a nitric oxide generator, molsidomine; and b) whether MDSC may partially counteract their own repair effects by stimulating the expression of myostatin, the main lipofibrotic agent in the muscle and inhibitor of muscle mass. Results MDSC: a) reduced mortality, and b) in the ischemic muscle, increased stem cell number and myofiber central nuclei, reduced fat infiltration, myofibroblast number, and myofiber apoptosis, and increased smooth muscle and endothelial cells, as well as neurotrophic factors. The content of myosin heavy chain 2 (MHC-2) myofibers was not restored and collagen was increased, in association with myostatin overexpression. Supplementation of MDSC with molsidomine failed to stimulate the beneficial effects of MDSC, except for some reduction in myostatin overexpression. Molsidomine given alone was rather ineffective, except for inhibiting apoptosis and myostatin overexpression. Conclusions MDSC improved CLI muscle repair, but molsidomine did not stimulate this process. The combination of MDSC with anti-myostatin approaches should be explored to restore myofiber MHC composition.

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Nitric Oxide-Dependent Neovascularization Role in the Lower Extremity Disease

Cited by 19 publications

References 48 publications

20-HETE contributes to ischemia-induced angiogenesis

20-HETE contributes to ischemia-induced angiogenesis

Treatment with Sildenafil and Donepezil Improves Angiogenesis in Experimentally Induced Critical Limb Ischemia

Muscle Derived Stem Cells Stimulate Muscle Myofiber Repair and Counteract Fat Infiltration in a Diabetic Mouse Model of Critical Limb Ischemia

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