Transforming growth factor‐beta 1 (TGF‐β1) induces angiogenesis through vascular endothelial growth factor (VEGF)‐mediated apoptosis

Ferrari, Giovanni; Cook, Brandoch D.; Terushkin, Vitaly; Pintucci, Giuseppe; Mignatti, Paolo

doi:10.1002/jcp.21706

Cited by 286 publications

(166 citation statements)

References 62 publications

(101 reference statements)

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“…While we cannot rule out AT1-mediated effects of losartan, we show that brain exposure to losartan indeed blocked TGF-β signaling, and reduced albumin-induced increase in p-Smad2/3 levels as well as astrocytic activation. As TGF-β1 was also shown to induce the activation of vascular endothelial growth factor (VEGF) signaling 53,54 , losartan may also prevent angiogenesis and BBB dysfunction- both known to contribute to the epileptogenic process 55,56 . These findings, along with reports that losartan decreases BBB permeability in hypertensive rats 57,58 , raise the possibility of a direct effect of losartan on endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Losartan prevents acquired epilepsy via TGF‐β signaling suppression

Bar‐Klein

Cacheaux

Kamintsky

et al. 2014

Annals of Neurology

235

221

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Objective Acquired epilepsy is frequently associated with structural lesions following trauma, stroke and infections. While seizures are often difficult to treat, there is no clinically applicable strategy to prevent the development of epilepsy in patients at risk. We have recently shown that vascular injury is associated with activation of albumin-mediated transforming growth factor β (TGF-β) signaling, and followed by local inflammatory response and epileptiform activity ex vivo. Here we investigated albumin-mediated TGF-β signaling and tested the efficacy of blocking the TGF-β pathway in preventing epilepsy. Methods We addressed the role of TGF-β signaling in epiletogenesis in two different rat models of vascular injury, combining in vitro and in vivo biochemical assays, gene expression, magnetic resonance and direct optical imaging for blood-brain barrier (BBB) permeability and vascular reactivity. Long-term electrocorticographic (ECoG) recordings were acquired in freely behaving animals. Results We demonstrate that serum-derived albumin preferentially induces activation of the activin receptor-like kinase 5 (ALK5) pathway of TGF-β receptor I in astrocytes. We further show that the angiotensin II type 1 receptor antagonist (AT1), losartan, previously identified as a blocker of peripheral TGF-β signaling, effectively blocks albumin-induced TGF-β activation in the brain. Most importantly, losartan prevents the development of delayed recurrent spontaneous seizures, an effect that persists weeks after drug withdrawal. Interpretation TGF-β signaling, activated in astrocytes by serum-derived albumin, is involved in epileptogenesis. We propose losartan, an FDA-approved drug, as an efficient anti-epileptogenic therapy for epilepsy associated with vascular injury.

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Section: Discussionmentioning

confidence: 99%

Losartan prevents acquired epilepsy via TGF‐β signaling suppression

Bar‐Klein

Cacheaux

Kamintsky

et al. 2014

Annals of Neurology

235

221

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“…Besides being a pro-fibrogenic cytokine, TGF-β has the ability to promote angiogenesis. VEGF and TGF-β interact closely with respect to angiogenic and fibrogenic effects (Ferrari et al, 2009). A recent in vitro study showed that SWCNT-induced fibroblast proliferation and collagen production is mediated by VEGF and TGF-β1 (Azad et al, 2012).…”

Section: Biological Activities Cntsmentioning

confidence: 99%

Pulmonary toxicity and fibrogenic response of carbon nanotubes

Manke

Wang

Rojanasakul

2013

Toxicology Mechanisms and Methods

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Carbon nanotubes (CNTs) have been a subject of intensive research for a wide range of applications. However, because of their extremely small size and light weight, CNTs are readily inhaled into human lungs resulting in increased rates of pulmonary disorders, most notably fibrosis. Several studies have demonstrated the fibrogenic effects of CNTs given their ability to translocate into the surrounding areas in the lung causing granulomatous lesions and interstitial and sub-pleural fibrosis. However, the mechanisms underlying the disease process remain obscure due to the lack of understanding of the cellular interactions and molecular targets involved. Interestingly, certain physicochemical properties of CNTs have been shown to affect their respiratory toxicity, thereby becoming significant determinants of fibrogenesis. CNT-induced fibrosis involves a multitude of cell types and is characterized by the early onset of inflammation, oxidative stress and accumulation of extracellular matrix. Increased reactive oxygen species activate various cytokine/growth factor signaling cascades resulting in increased expression of inflammatory and fibrotic genes. Profibrotic growth factors and cytokines contribute directly to fibroblast proliferation and collagen production. Given the role of multiple players during the pathogenesis of CNT-induced fibrosis, the objective of this review is to summarize the key findings and discuss major cellular and molecular events governing pulmonary fibrosis. We also discuss the physicochemical properties of CNTs and their effects on pulmonary toxicities as well as various biological factors contributing to the development of fibrosis.

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“…Further, in vitro approaches can leverage the epitope of sequestering to design bioactive substrates that promote EC pro-angiogenic function. For example, during angiogenesis, VEGF elicits a pro-angiogenic response 181 whereas high levels of TGF-β1 can inhibit angiogenesis 182,183 . Thus, surfaces that can simultaneously up-regulate VEGF activity (via allosteric sequestering) and down-regulate TGF-β1 activity (via active site sequestering) could, in principle, promote EC pro-angiogenic function at the sequestering interface.…”

Section: Introductionmentioning

confidence: 99%

Design of growth factor sequestering biomaterials

Belair

2014

Chem. Commun.

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Growth factors (GFs) are major regulatory proteins that can govern cell fate, migration, and organization. Numerous aspects of the cell milieu can modulate cell responses to GFs, and GF regulation is often achieved by the native extracellular matrix (ECM). For example, the ECM can sequester GFs and thereby control GF bioavailability. In addition, GFs can exert distinct effects depending on whether they are sequestered in solution, at two-dimensional interfaces, or within three-dimensional matrices. Understanding how the context of GF sequestering impacts cell function in the native ECM can instruct the design of soluble or insoluble GF sequestering moieties, which can then be used in a variety of bioengineering applications. This Feature Article provides an overview of the natural mechanisms of GF sequestering in the cell milieu, and reviews the recent bioengineering approaches that have sequestered GFs to modulate cell function. Results to date demonstrate that the cell response to GF sequestering depends on the affinity of the sequestering interaction, the spatial proximity of sequestering in relation to cells, the source of the GF (supplemented or endogenous), and the phase of the sequestering moiety (soluble or insoluble). We highlight the importance of context for the future design of biomaterials that can leverage endogenous molecules in the cell milieu and mitigate the need for supplemented factors.

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Transforming growth factor‐beta 1 (TGF‐β1) induces angiogenesis through vascular endothelial growth factor (VEGF)‐mediated apoptosis

Cited by 286 publications

References 62 publications

Losartan prevents acquired epilepsy via TGF‐β signaling suppression

Losartan prevents acquired epilepsy via TGF‐β signaling suppression

Pulmonary toxicity and fibrogenic response of carbon nanotubes

Design of growth factor sequestering biomaterials

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