Neurotrophin p75 Receptor (p75NTR) Promotes Endothelial Cell Apoptosis and Inhibits Angiogenesis: Implications for Diabetes-Induced Impaired Neovascularization in Ischemic Limb Muscles (original) (raw)
Related papers
Circulation …, 2008
Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75 NTR), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75 NTR expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75 NTR gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75 NTR depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin], BIRC5 (survivin), PTTG1 (securin) and VEZF1. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75 NTR. Collectively, our data newly demonstrate the antiangiogenic action of p75 NTR and open new avenues for the therapeutic use of p75 NTR inhibition to combat diabetes-induced microvascular liabilities.
Tumor Necrosis Factor Receptor p75 Is Required in Ischemia-Induced Neovascularization
Circulation, 2007
Background-Aging is a risk factor for coronary and peripheral artery disease. Tumor necrosis factor-␣ (TNF-␣), a proinflammatory cytokine, is expressed in ischemic tissue and is known to modulate angiogenesis. Little is known about the role of TNF-␣ receptors (TNFR1/p55 and TNFR2/p75) in angiogenic signaling. Methods and Results-We studied neovascularization in the hindlimb ischemia model in young and old TNFR2/p75 knockout (p75KO) and wild-type age-matched controls. Between days 7 to 10 after hindlimb surgery, 100% of old p75KOs experienced autoamputation of the operated limbs, whereas none of the age-matched wild-type mice exhibited hindlimb necrosis. Poor blood flow recovery in p75KO mice was associated with increased endothelial cell apoptosis, decreased capillary density, and significant reductions in the expression of vascular endothelial growth factor and basic fibroblast growth factor-2 mRNA transcripts in ischemic tissue and in circulating endothelial progenitor cells. The number of circulating bone marrow-derived endothelial progenitor cells was significantly reduced in p75KO mice. Transplantation of wild-type bone marrow mononuclear cells into irradiated old p75KO mice 1 month before hindlimb surgery prevented limb loss.
Journal of diabetes, metabolic disorders & control, 2017
Diabetic retinopathy is characterized by early stage of retinal neuro-inflammation that triggers development of acellular capillaries and a late stage of pathological neovascularization. Due to limited treatment options, there is a pressing need to develop new therapeutics. Our group discovered that diabetes-impaired processing of the nerve growth factor precursor (proNGF) resulting in its accumulation and its receptor p75. Here, we examine the protective effects of modulating p75 in experimental model of diabetic retinopathy. Diabetes was induced using streptozotocin in both wild type (WT) and p75 knockout (p75KO) mice. Retinal inflammation and microvascular dysfunction were assessed. Western blot analysis was performed to assess expression of apoptotic and inflammatory markers and levels of the neurotrophin, p75 and ephrin-B2. Deletion of p75 did not alter body weight or diabetes status compared to WT mice. In WT-mice, diabetes triggered retinal inflammation, significant decrease ...
British Journal of Pharmacology, 2007
Background and purpose:Mature endothelial cells and their progenitors are dysfunctional in diabetes, resulting in deficient neovascularisation following arterial occlusion. This study aimed to evaluate the therapeutic activity of a nitric oxide (NO) releasing statin in the setting of experimental diabetes and peripheral ischaemia.Mature endothelial cells and their progenitors are dysfunctional in diabetes, resulting in deficient neovascularisation following arterial occlusion. This study aimed to evaluate the therapeutic activity of a nitric oxide (NO) releasing statin in the setting of experimental diabetes and peripheral ischaemia.Experimental approach:The effects of NCX 6550, an NO-releasing pravastatin derivative, on angiogenesis in ischaemic limbs was studied in normoglycaemic mice or mice made diabetic by treatment with streptozotocin (STZ). Control mice received an equimolar dosage of the parent statin compound, pravastatin. The therapeutic action of NCX 6550 was also tested in mice lacking the gene for endothelial nitric oxide synthase (eNOS).The effects of NCX 6550, an NO-releasing pravastatin derivative, on angiogenesis in ischaemic limbs was studied in normoglycaemic mice or mice made diabetic by treatment with streptozotocin (STZ). Control mice received an equimolar dosage of the parent statin compound, pravastatin. The therapeutic action of NCX 6550 was also tested in mice lacking the gene for endothelial nitric oxide synthase (eNOS).Key Results:In normoglycaemic or STZ-diabetic CD1 mice, only NCX 6550 stimulated skeletal muscle revascularisation. In addition, NCX 6550 induced greater improvement in limb reperfusion and salvage, than pravastatin. The number of circulating endothelial progenitor cells was decreased in STZ-diabetic mice, this defect being prevented by NCX 6550 and, to a lesser extent by pravastatin. In vitro, high glucose concentrations reduced the migratory capacity of endothelial progenitor EPCs, which was partly reversed by preincubation with pravastatin and completely reversed by NCX 6550. The postischaemic recovery of eNOS knockout mice was severely impaired as a consequence of depressed angiogenesis and this recovery was improved by treatment with NCX 6550, but not with pravastatin.In normoglycaemic or STZ-diabetic CD1 mice, only NCX 6550 stimulated skeletal muscle revascularisation. In addition, NCX 6550 induced greater improvement in limb reperfusion and salvage, than pravastatin. The number of circulating endothelial progenitor cells was decreased in STZ-diabetic mice, this defect being prevented by NCX 6550 and, to a lesser extent by pravastatin. In vitro, high glucose concentrations reduced the migratory capacity of endothelial progenitor EPCs, which was partly reversed by preincubation with pravastatin and completely reversed by NCX 6550. The postischaemic recovery of eNOS knockout mice was severely impaired as a consequence of depressed angiogenesis and this recovery was improved by treatment with NCX 6550, but not with pravastatin.Conclusions and implications:These findings indicate that incorporation of a bioactive NO moiety improves the therapeutic profile of statins for the treatment of peripheral vascular disease.British Journal of Pharmacology (2007) 150, 873–882. doi:10.1038/sj.bjp.0707142These findings indicate that incorporation of a bioactive NO moiety improves the therapeutic profile of statins for the treatment of peripheral vascular disease.British Journal of Pharmacology (2007) 150, 873–882. doi:10.1038/sj.bjp.0707142
Nature communications, 2015
The communication between vascular endothelial cells (ECs) and pericytes in the microvasculature is fundamental for vascular growth and homeostasis; however, these processes are disrupted by diabetes. Here we show that modulation of p75(NTR) expression in ECs exposed to high glucose activates transcription of miR-503, which negatively affects pericyte function. p75(NTR) activates NF-κB to bind the miR-503 promoter and upregulate miR-503 expression in ECs. NF-κB further induces activation of Rho kinase and shedding of endothelial microparticles carrying miR-503, which transfer miR-503 from ECs to vascular pericytes. The integrin-mediated uptake of miR-503 in the recipient pericytes reduces expression of EFNB2 and VEGFA, resulting in impaired migration and proliferation. We confirm operation of the above mechanisms in mouse models of diabetes, in which EC-derived miR-503 reduces pericyte coverage of capillaries, increased permeability and impaired post-ischaemic angiogenesis in limb m...
Diabetes impairs arteriogenesis in the peripheral circulation: review of molecular mechanisms
Clinical Science, 2010
Patients suffering from both diabetes and PAD (peripheral arterial disease) are at risk of developing critical limb ischaemia and ulceration, and potentially requiring limb amputation. In addition, diabetes complicates surgical treatment of PAD and impairs arteriogenesis. Arteriogenesis is defined as the remodelling of pre-existing arterioles into conductance vessels to restore the perfusion distal to the occluded artery. Several strategies to promote arteriogenesis in the peripheral circulation have been devised, but the mechanisms through which diabetes impairs arteriogenesis are poorly understood. The present review provides an overview of the current literature on the deteriorating effects of diabetes on the key players in the arteriogenesis process. Diabetes affects arteriogenesis at a number of levels. First, it elevates vasomotor tone and attenuates sensing of shear stress and the response to vasodilatory stimuli, reducing the recruitment and dilatation of collateral arteries. Secondly, diabetes impairs the downstream signalling of monocytes, without decreasing monocyte attraction. In addition, EPC (endothelial progenitor cell) function is attenuated in diabetes. There is ample evidence that growth factor signalling is impaired in diabetic arteriogenesis. Although these defects could be restored in animal experiments, clinical results have been disappointing. Furthermore, the diabetes-induced impairment of eNOS (endothelial NO synthase) strongly affects outward remodelling, as NO signalling plays a key role in several remodelling processes. Finally, in the structural phase of arteriogenesis, diabetes impairs matrix turnover, smooth muscle cell proliferation and fibroblast migration. The review concludes with suggestions for new and more sophisticated therapeutic approaches for the diabetic population.
Molecular Therapy — Methods & Clinical Development, 2015
Accumulation of the nerve growth factor precursor (proNGF) and its receptor p75 NTR have been associated with several neurodegenerative diseases in both brain and retina. However, whether proNGF contributes to microvascular degeneration remain unexplored. This study seeks to investigate the mechanism by which proNGF/p75 NTR induce endothelial cell (EC) death and development of acellular capillaries, a surrogate marker of retinal ischemia. Stable overexpression of the cleavage-resistant proNGF and molecular silencing of p75 NTR were utilized in human retinal EC and rat retinas in vivo. Stable overexpression of proNGF decreased NGF levels and induced retinal vascular cell death evident by 1.9-fold increase in acellular capillaries and activation of JNK and cleaved-PARP that were mitigated by p75 NTR shRNA. In vitro, overexpression of proNGF did not alter TNF-α level, reduced NGF, however induced EC apoptosis evident by activation of JNK and p38 MAPK, cleaved-PARP. Silencing p75 NTR using siRNA restored expression of NGF and TrkA activation and prevented EC apoptosis. Treatment of EC with human-mutant proNGF induced apoptosis that coincided with marked protein interaction and nuclear translocation of p75 NTR and the neurotrophin receptor interacting factor. These effects were abolished by a selective p75 NTR antagonist. Therefore, targeting p75 NTR represents a potential therapeutic strategy for diseases associated with aberrant expression of proNGF.
p75NTR Mediates Neurotrophin-Induced Apoptosis of Vascular Smooth Muscle Cells
The American Journal of Pathology, 2000
The development of atherosclerotic lesions results from aberrant cell migration, proliferation, and extracellular matrix production. In advanced lesions, however, cellular apoptosis, leading to lesion remodeling, predominates. During lesion formation, the neurotrophins and the neurotrophin receptor tyrosine kinases, trks B and C, are induced and mediate smooth muscle cell migration. Here we demonstrate that a second neurotrophin receptor, p75 NTR , is expressed by established human atherosclerotic lesions and late lesions that develop after balloon injury of the rat thoracic aorta. The p75 NTR , a member of the tumor necrosis factor/FAS receptor family, can modulate trk receptor function as well as initiate cell death when expressed in cells of the nervous system that lack kinase-active trk receptors. p75 NTR expression colocalizes to neointimal cells, which express smooth muscle cell ␣-actin and are expressed by cultured human endarterectomy-derived cells (HEDC). Areas of the plaque expressing p75 NTR demonstrate increased TUNEL positivity, and HEDC undergo apoptosis in response to the neurotrophins. Finally, neurotrophins also induced apoptosis of a smooth muscle cell line genetically manipulated to express p75 NTR , but lacking trk receptor expression. These studies identify the regulated expression of neurotrophins and p75 NTR as an inducer of smooth muscle cell apoptosis in atherosclerotic lesions. The neurotrophins are a family of highly conserved growth factors best characterized for their critical roles in the differentiation and survival of neurons, via activation of two classes of receptors. The trk receptor tyrosine kinases, including trk A, trk B, and trk C, bind selectively to distinct neurotrophins, with nerve growth factor (NGF) binding trk A, brain-derived neurotrophic factor (BDNF) binding trk B, and neurotrophin-3 (NT-3) binding trk C.
2021
Mesenchymal stem cells (MSCs) are a promising therapy to improve vascular repair, yet their role in ischemic retinopathy is not fully understood. The aim of this study is to investigate the impact of modulating the neurotrophin receptor; p75NTR on the vascular protection of MSCs in an acute model of retinal ischemia/reperfusion (I/R). Wild type (WT) and p75NTR-/- mice were subjected to I/R injury by increasing intra-ocular pressure to 120 mmHg for 45 min, followed by perfusion. Murine GFP-labeled MSCs (100,000 cells/eye) were injected intravitreally 2 days post-I/R and vascular homing was assessed 1 week later. Acellular capillaries were counted using trypsin digest 10-days post-I/R. In vitro, MSC-p75NTR was modulated either genetically using siRNA or pharmacologically using the p75NTR modulator; LM11A-31, and conditioned media were co-cultured with human retinal endothelial cells (HREs) to examine the angiogenic response. Finally, visual function in mice undergoing retinal I/R and ...