Transforming growth factor-beta 1 produced by vascular smooth muscle cells predicts fibrosis in the gastrocnemius of patients with peripheral artery disease

Ha, Duy M.; Carpenter, Lauren C.; Koutakis, Panagiotis; Swanson, Stanley A.; Zhu, Zhen; Hanna, Mina; DeSpiegelaere, Holly; Pipinos, Iraklis I.; Casale, George P.

doi:10.1186/s12967-016-0790-3

Cited by 49 publications

(73 citation statements)

References 52 publications

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“…These deficits appear related to the neuropathy and myopathy previously described by our group 2–4,11,27–28 and others. 5–6,31–33 Our work demonstrates that there are functional tests, including the maximal isometric plantar flexion test we are describing in this paper, that can measure and stratify the degree of impairment in the legs of patients with PAD.…”

Section: Discussionsupporting

confidence: 79%

“…The strength differences between Controls and PAD when subjects perform a 10 seconds isometric test immediately after rest and before any exercise-induced ischemia/pain confirm that the weakness in the PAD ankle plantar flexors is related to the well described myopathy of PAD. 2,4,9,11,27–28 Furthermore, the introduction of ischemic claudication symptoms altered the motor control strategies of the ankle plantar flexors producing significant differences between PAD conditions.…”

Section: Discussionmentioning

confidence: 99%

“…31–33 The myopathy in patients with PAD involves defective mitochondrial bioenergetics, oxidative damage, myofiber degeneration and fibrosis of the affected skeletal muscles. 2–6,11,27–28,34–35 Increased oxidative damage in PAD muscle is associated with deterioration of the size and shape of myofibers in the gastrocnemius with preference for Type II myofibers while Type I fibers persist and are less damaged. 9 Type II fibers are high-energy consumers and are utilized in short explosive movements such as the isometric contraction.…”

Section: Discussionmentioning

confidence: 99%

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Muscle strength and control characteristics are altered by peripheral artery disease

Schieber

Hasenkamp

Pipinos

et al. 2017

Journal of Vascular Surgery

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Objective Peripheral Artery Disease (PAD) is a common manifestation of atherosclerosis, characterized by lower leg ischemia and myopathy in association with leg dysfunction. Patients with PAD have impaired gait from the first step they take with consistent defects in the movement around the ankle joint especially in plantar flexion. Our goal was to develop muscle strength profiles to better understand the problems in motor control responsible for the walking impairment in patients with PAD. Methods Ninety-four claudicating PAD patients performed maximal isometric plantar flexion contractions lasting 10s in two conditions: pain-free (patient is well rested and has no claudication symptoms) and pain-induced (patient has walked and has claudication symptoms). Sixteen matched healthy Controls performed the pain-free condition only. Torque curves were analyzed for dependent variables of muscle strength and motor control. Independent t tests were used to compare variables between groups and dependent t tests determined differences between conditions. Results Patients with PAD had significantly reduced peak torque and Area Under the Curve compared to Controls. Measures of control differed between PAD conditions only. Load rate and Linear Region Duration were greater in the pain condition. Time to peak torque was shorter in the pain condition. Conclusions The current study conclusively demonstrates that the plantar flexor muscles of the PAD patient at baseline and without pain are weaker in patients with PAD compared to Controls. With the onset of claudication pain, patients with PAD exhibit altered muscle control strategies and further strength deficits are manifest compared to baseline levels. The myopathy of PAD legs appears to have a central role in the functional deterioration of the calf muscles, as it is evident both before and after onset of ischemic pain.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Muscle strength and control characteristics are altered by peripheral artery disease

Schieber

Hasenkamp

Pipinos

et al. 2017

Journal of Vascular Surgery

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“…Research has suggested a detrimental role of TGFβ signaling in the progression of PAD by measuring the levels of TGFβ and its receptors in ischemic tissues and in peripheral blood collected from patients [104–106]. We are interested in the effect of TGFβ-induced TSP-1 synthesis and potential interventions to reduce TSP-1 in both normoxic and hypoxic conditions, since TSP-1 levels are found upregulated in PAD patients [13, 107].…”

Section: Resultsmentioning

confidence: 99%

“…Although the regulatory roles of TSP-1 in tumor progression is highly cell-type specific, the undesirable anti-angiogenic effect resulting from high TSP-1 expression in PAD is a major interest to cardiologists and vascular biologists [107, 137, 138]. Our model proposed that TGFβ might be an underlying factor driving the high expressions of TSP-1 in PAD patients, given the experimental evidence of TGFβ1 elevation in ischemic tissues [106, 139]. It is interesting to note that hypoxia also upregulates TGFβ1 production in smooth muscle cells in addition to the direct transcriptional induction of TSP-1 via HIFs, suggesting another layer of crosstalk between the pathways that control TSP-1 expression [14].…”

Section: Discussionmentioning

confidence: 99%

Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model

2017

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Hypoxia is an important physiological stress signal that drives angiogenesis, the formation of new blood vessels. Besides an increase in the production of pro-angiogenic signals such as vascular endothelial growth factor (VEGF), hypoxia also stimulates the production of anti-angiogenic signals. Thrombospondin-1 (TSP-1) is one of the anti-angiogenic factors whose synthesis is driven by hypoxia. Cellular synthesis of TSP-1 is tightly regulated by different intermediate biomolecules including proteins that interact with hypoxia-inducible factors (HIFs), transcription factors that are activated by receptor and intracellular signaling, and microRNAs which are small non-coding RNA molecules that function in post-transcriptional modification of gene expression. Here we present a computational model that describes the mechanistic interactions between intracellular biomolecules and cooperation between signaling pathways that together make up the complex network of TSP-1 regulation both at the transcriptional and post-transcriptional level. Assisted by the model, we conduct in silico experiments to compare the efficacy of different therapeutic strategies designed to modulate TSP-1 synthesis in conditions that simulate tumor and peripheral arterial disease microenvironment. We conclude that TSP-1 production in endothelial cells depends on not only the availability of certain growth factors but also the fine-tuned signaling cascades that are initiated by hypoxia.

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Interventional‐ and amputation‐stage muscle proteomes in the chronically threatened ischemic limb

Ryan

Kim

Scali

et al. 2022

Clinical & Translational Med

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Background Despite improved surgical approaches for chronic limb‐threatening ischemia (CLTI), amputation rates remain high and contributing tissue‐level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation. Methods and results Gastrocnemius muscle was collected from non‐ischemic controls (n = 19) and either pre‐interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem‐mass‐tag‐assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre‐interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre‐intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non‐ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. Conclusions The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre‐intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI.

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Transforming growth factor-beta 1 produced by vascular smooth muscle cells predicts fibrosis in the gastrocnemius of patients with peripheral artery disease

Cited by 49 publications

References 52 publications

Muscle strength and control characteristics are altered by peripheral artery disease

Muscle strength and control characteristics are altered by peripheral artery disease

Transcriptional and Post-Transcriptional Regulation of Thrombospondin-1 Expression: A Computational Model

Interventional‐ and amputation‐stage muscle proteomes in the chronically threatened ischemic limb

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