Abstract No. 295: Hypoxia induces a phenotypic switch of fibroblasts to myofibroblasts through a MMP-2/TIMP mediated pathway: Implications for venous stenosis formation in hemodialysis vascular access failure

Misra, Sanjay; Fu, Alex A.; Misra, Khamal D.; Shergill, Uday

doi:10.1016/j.jvir.2009.12.083

Cited by 3 publications

(5 citation statements)

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“…HIF‐1α also stimulates the expression of fibroblast growth factor (FGF), which induces proliferation and differentiation of fibroblasts . In murine fibroblasts subjected to hypoxia, HIF‐1α converts fibroblasts to myofibroblasts through a MMP2/TIMP mediated pathway . In addition, HIF‐1α induces the expression of multiple other profibrotic genes including thrombospondin (TSP1), pro α2 (I) collagen (COLIA2), transforming growth factor β (TGF‐β), NADPH oxidase (NOX), transforming growth factor β‐induced protein (TGF‐β1), and connective tissue growth factor (CTGF) .…”

Section: Adipose Tissue Fibrosis and Inflammationmentioning

confidence: 99%

“…68,72 In murine fibroblasts subjected to hypoxia, HIF-1α converts fibroblasts to myofibroblasts through a MMP2/TIMP mediated pathway. 74 In addition, HIF-1α induces the expression of multiple other profibrotic genes including thrombospondin (TSP1), pro α2 (I) collagen (COLIA2), transforming growth factor β (TGF-β), NADPH oxidase (NOX), transforming growth factor β-induced protein (TGF-β1), and connective tissue growth factor (CTGF). 75 Thrombospondins play an important role in regulating cell to cell and cell to extracellular matrix (ECM) interactions.…”

Section: Adipose Tissue Fibrosis and Inflammationmentioning

confidence: 99%

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Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

Warbrick

Rabkin

2019

Obesity Reviews

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Summary Heart failure with preserved ejection fraction (HFpEF), a common condition with an increased mortality, is strongly associated with obesity and the metabolic syndrome. The latter two conditions are associated with increased epicardial fat that can extend into the heart. This review advances the proposition that hypoxia‐inhibitory factor‐1α (HIF‐1α) maybe a key factor producing HFpEF. HIF‐1α, a highly conserved transcription factor that plays a key role in tissue response to hypoxia, is increased in adipose tissue in obesity. Increased HIF‐1α expression leads to expression of a potent profibrotic transcriptional programme involving collagen I, III, IV, TIMP, and lysyl oxidase. The net effect is the formation of collagen fibres leading to fibrosis. HIF‐1α is also responsible for recruiting M1 macrophages that mediate obesity‐associated inflammation, releasing IL‐6, MCP‐1, TNF‐α, and IL‐1β with increased expression of thrombospondin, pro α2 (I) collagen, transforming growth factor β, NADPH oxidase, and connective tissue growth factor. These factors can accelerate cardiac fibrosis and impair cardiac diastolic function. Inhibition of HIF‐1α expression in adipose tissue of mice fed a high‐fat diet suppressed fibrosis and reduces inflammation in adipose tissue. Delineation of the role played by HIF‐1α in obesity‐associated HFpEF may lead to new potential therapies.

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Section: Adipose Tissue Fibrosis and Inflammationmentioning

confidence: 99%

Section: Adipose Tissue Fibrosis and Inflammationmentioning

confidence: 99%

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

Warbrick

Rabkin

2019

Obesity Reviews

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“…In various types of mammalian cells, specific factors that support myogenic gene expression patterns and phenotypes include low-serum growth conditions (Desmoulière et al, 1993), growth on collagen IV (Gong & Niklason, 2008), culture in the presence of TGF-β1 (Arciniegas et al, 1992;Chambers et al, 2003;Desmoulière et al, 1993;Verrecchia et al, 2001) and culture under hypoxia (Misra et al, 2010;Robinson et al, 2012;Short et al, 2004;Wang et al, 2012). These factors influenced our choice for the differentiation conditions under which to culture human dermal fibroblasts towards the goal of stimulating gene expression and protein synthesis characteristic of SMC-like phenotypes.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, we set out to investigate whether the combination of these factors (low serum, collagen IV and TGF‐β1) was sufficient to shift the phenotype and gene expression patterns of human dermal fibroblasts towards a more SMC‐like state. In addition, as several reports have implicated hypoxia in the modulation of myogenic gene expression and phenotype (Misra et al, ; Robinson, Neary, Levendale, Watson, & Baugh, ; Short, Nemenoff, Zawada, Stenmark, & Das, ; Wang, Sun, Xue, & Jiang, ), including via regulation of the myogenic transcription factor myocardin, and due to our own previous work demonstrating that hypoxia can contribute to phenotypic shifts in human dermal fibroblasts, we decided to investigate hypoxia as another potential factor for induction of SMC‐like gene expression patterns and phenotypes in human dermal fibroblasts. In the present study, we evaluated culture conditions shown to promote and/or maintain myogenic phenotypes in SMCs, including culture under low oxygen, and assessed their effects on acquisition of SMC‐like gene expression patterns in human dermal fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Pro‐myogenic and low‐oxygen culture increases expression of contractile smooth muscle markers in human fibroblasts

Veber

Dolivo

Rolle

et al. 2017

J Tissue Eng Regen Med

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Smooth muscle cells (SMCs) are essential for tissue engineering strategies to fabricate organs such as blood vessels, the oesophagus and bladder, and to create disease models of these systems. In order for such therapies and models to be feasible, SMCs must be sourced effectively to enable production of large numbers of functional cells. In vitro, SMCs divide slowly and demonstrate short proliferative lifespans compared with other types of cells, including stem cells and fibroblasts, limiting the number of cells that can be derived from expansion in culture of a primary isolation. As such, it would be beneficial to better understand the factors underlying induction and maintenance of SMC phenotypes, in order to produce new sources of SMCs for tissue engineering and disease modelling. Here we report the ability of human dermal fibroblasts to display patterns of gene expression resembling contractile SMCs when cultured under conditions that are known to promote a contractile phenotype in SMCs, including culture on collagen IV, low-serum culture, TGF-β1 treatment and hypoxia. These factors drive expression of the myogenic transcription factor myocardin, as well as expression of several of its gene targets that are known contributors to contractile phenotype in SMCs, including smooth muscle alpha actin, calponin, and myosin heavy chain. Our results suggest that culture conditions associated with culture of SMCs may be sufficient to induce myogenic gene expression patterns and potential myogenic function in non-muscle cells.

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“…Adventitial angiogenesis, an outward remodeling process by which new tissue and microvessels form on the outer, adventitial layer of vein walls, is thought to be beneficial for veins surgically connected to the arterial circulation because it can cause the outward instead of inward migration of VSMCs and myofibroblasts to mitigate NH (Angelini, Izzat, Bryan, & Newby, 1996; George et al, 2001; Jeremy et al, 2007; Mehta et al, 1998). Neovascularization (as well as accumulation of immune cells such as lymphocytes and neutrophils) induced by perivascular wraps comprised of nondegradable Dacron (Angelini et al, 1996; George et al, 2001; Jeremy et al, 2007; Mehta et al, 1998) or fast‐degrading (i.e., 1–2 month loss of strength) polyglactin (Jeremy et al, 2004; Maurus & Kaeding, 2004; Vijayan et al, 2004) may have reduced NH by serving as chemoattractants in the interstitial space between external stent and venous tissue, as well as by restoring a small blood vessel network akin to the vein's native vasa vasorum (i.e., neovasa vasorum) that may mitigate NH‐inducing hypoxic conditions (Chanakira et al, 2012; McGeachie, Meagher, & Prendergast, 1989; Misra et al, 2010) and is particularly disrupted in PABG and CABG surgeries (Jeremy et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Effect of pore size and spacing on neovascularization of a biodegradble shape memory polymer perivascular wrap

Boire

Himmel

et al. 2020

J Biomedical Materials Res

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Neointimal hyperplasia (NH) is a main source of failures in arteriovenous fistulas and vascular grafts. Several studies have demonstrated the promise of perivascular wraps to reduce NH via promotion of adventitial neovascularization and providing mechanical support. Limited clinical success thus far may be due to inappropriate material selection (e.g., nondegradable, too stiff) and geometric design (e.g., pore size and spacing, diameter). The influence of pore size and spacing on implant neovascularization is investigated here for a new biodegradable, thermoresponsive shape memory polymer (SMP) perivascular wrap. Following an initial pilot, 21 mice were each implanted with six scaffolds: four candidate SMP macroporous designs (a–d), a nonporous SMP control (e), and microporous GORETEX (f). Mice were sacrificed after 4 (N = 5), 14 (N = 8), and 28 (N = 8) days. There was a statistically significant increase in neovascularization score between all macroporous groups compared to nonporous SMP (p < .023) and microporous GORETEX (p < .007) controls at Day 28. Wider‐spaced, smaller‐sized pore designs (223 μm‐spaced, 640 μm‐diameter Design c) induced the most robust angiogenic response, with greater microvessel number (p < .0114) and area (p < .0055) than nonporous SMPs and GORETEX at Day 28. This design also produced significantly greater microvessel density than nonporous SMPs (p = 0.0028) and a smaller‐spaced, larger‐sized pore (155 μm‐spaced, 1,180 μm‐sized Design b) design (p = .0013). Strong neovascularization is expected to reduce NH, motivating further investigation of this SMP wrap with controlled pore spacing and size in more advanced arteriovenous models.

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Abstract No. 295: Hypoxia induces a phenotypic switch of fibroblasts to myofibroblasts through a MMP-2/TIMP mediated pathway: Implications for venous stenosis formation in hemodialysis vascular access failure

Cited by 3 publications

References 0 publications

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

Hypoxia‐inducible factor 1‐alpha (HIF‐1α) as a factor mediating the relationship between obesity and heart failure with preserved ejection fraction

Pro‐myogenic and low‐oxygen culture increases expression of contractile smooth muscle markers in human fibroblasts

Effect of pore size and spacing on neovascularization of a biodegradble shape memory polymer perivascular wrap

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