Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits

He, Yang; Liu, Jin; Guo, Baosheng; Wáng, Yì Xiáng J.; Pan, Xiaohua; Li, Defang; Tang, Tao; Yang, Chen; Peng, Songlin; Bian, Zhaoxiang; Liang, Zicai; Zhang, Bao-Ting; Lu, Aiping; Zhang, Ge

doi:10.1038/srep08856

Cited by 6 publications

(5 citation statements)

References 48 publications

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“…While there have been contradicting reports about the role of Akt in endothelial‐barrier regulation, our recent study has demonstrated the integral role of Akt1 in the long‐term protection of endothelial‐barrier in response to VEGF and Ang‐1 (Gao et al, ). The src family of non‐receptor tyrosine kinases has been implicated in vascular permeability and injury (He et al, ; Paul et al, ). Following ischemia and injury, phosphorylation of Src is highly upregulated causing activation of downstream signaling to induce barrier breakdown and vascular permeability (Esser, Lampugnani, Corada, Dejana, & Risau, ; Ha et al, ).…”

Section: Discussionmentioning

confidence: 99%

Modulation of long‐term endothelial‐barrier integrity is conditional to the cross‐talk between Akt and Src signaling

Gao

Sabbineni

Artham

et al. 2017

Journal Cellular Physiology

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Although numerous studies have implicated Akt and Src kinases in vascular endothelial growth factor (VEGF) and Angiopoietin-1 (Ang-1)-induced endothelial-barrier regulation, a link between these two pathways has never been demonstrated. We determined the long-term effects of Akt inhibition on Src activity and vice versa, and in turn, on the human microvascular endothelial cell (HMEC) barrier integrity at the basal level, and in response to growth factors. Our data showed that Akt1 gene knockdown increases gap formation in HMEC monolayer at the basal level. Pharmacological inhibition of Akt, but not Src resulted in exacerbated VEGF-induced vascular leakage and impaired Ang-1-induced HMEC-barrier protection in-vitro at 24 hours. Whereas inhibition of Akt had no effect on VEGF-induced HMEC gap formation in the short term, inhibition of Src blunted this process. In contrast, inhibition of Akt disrupted the VEGF and Ang-1 stabilized barrier integrity in the long-term while inhibition of Src did not. Interestingly, both long-term Akt inhibition and Akt1 gene knockdown in HMECs resulted in increased Tyr416 phosphorylation of Src. Treatment of HMECs with transforming growth factor-β1 (TGFβ1) that inhibited Akt Ser473 phosphorylation in the long-term, activated Src through increased Tyr416 phosphorylation and decreased HMEC-barrier resistance. The effect of TGFβ1 on endothelial-barrier breakdown was blunted in Akt1 deficient HMEC monolayers, where endothelial-barrier resistance was already impaired compared to the control. To our knowledge, this is the first report demonstrating a direct cross-talk between Akt and Src in endothelial-barrier regulation.

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Section: Discussionmentioning

confidence: 99%

Modulation of long‐term endothelial‐barrier integrity is conditional to the cross‐talk between Akt and Src signaling

Gao

Sabbineni

Artham

et al. 2017

Journal Cellular Physiology

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“…In contrast, periosteal lamellar bone deposition occurs much more slowly, in agreement with a progression of melorheostotic lesions over years . Periosteal new bone formation is often viewed as a physiological response to focal insults or systemic condition such as infections, hemorrhages, inflammations (periostitis), osteonecrosis, tumor processes, and malign neoplasms such as Ewing's sarcoma or Caffey's disease . In fact, so‐called “periosteal reactions” occur widely and represent a rather nonspecific mechanism to maintain bone strength, counteracting the effects of cortical lysis or endocortical bone loss by forming a bridge over damaged cortical area .…”

Section: Discussionmentioning

confidence: 96%

“…(44,46,47) Periosteal new bone formation is often viewed as a physiological response to focal insults or systemic condition such as infections, hemorrhages, inflammations (periostitis), osteonecrosis, tumor processes, and malign neoplasms such as Ewing's sarcoma or Caffey's disease. (13,(48)(49)(50)(51) In fact, so-called "periosteal reactions" occur widely and represent a rather nonspecific mechanism to maintain bone strength, counteracting the effects of cortical lysis or endocortical bone loss by forming a bridge over damaged cortical area. (13) Activating MAP2K1 mutations lead to highly proliferative osteoblasts, poor matrix mineralization, accelerated bone remodeling, and highly increased osteoclastogenesis.…”

Section: Discussionmentioning

confidence: 99%

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

Fratzl‐Zelman

Roschger

Kang

et al. 2019

Journal of Bone and Mineral Research

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Melorheostosis is a rare non‐hereditary condition characterized by dense hyperostotic lesions with radiographic “dripping candle wax” appearance. Somatic activating mutations in MAP2K1 have recently been identified as a cause of melorheostosis. However, little is known about the development, composition, structure, and mechanical properties of the bone lesions. We performed a multi‐method phenotype characterization of material properties in affected and unaffected bone biopsy samples from six melorheostosis patients with MAP2K1 mutations. On standard histology, lesions show a zone with intensively remodeled osteonal‐like structure and prominent osteoid accumulation, covered by a shell formed through bone apposition, consisting of compact multi‐layered lamellae oriented parallel to the periosteal surface and devoid of osteoid. Compared with unaffected bone, melorheostotic bone has lower average mineralization density measured by quantitative backscattered electron imaging (CaMean: –4.5%, p = 0.04). The lamellar portion of the lesion is even less mineralized, possibly because the newly deposited material has younger tissue age. Affected bone has higher porosity by micro‐CT, due to increased tissue vascularity and elevated 2D‐microporosity (osteocyte lacunar porosity: +39%, p = 0.01) determined on quantitative backscattered electron images. Furthermore, nano‐indentation modulus characterizing material hardness and stiffness was strictly dependent on tissue mineralization (correlation with typical calcium concentration, CaPeak: r = 0.8984, p = 0.0150, and r = 0.9788, p = 0.0007, respectively) in both affected and unaffected bone, indicating that the surgical hardness of melorheostotic lesions results from their lamellar structure. The results suggest a model for pathophysiology of melorheostosis caused by somatic activating mutations in MAP2K1, in which the genetically induced gradual deterioration of bone microarchitecture triggers a periosteal reaction, similar to the process found to occur after bone infection or local trauma, and leads to an overall cortical outgrowth. The micromechanical properties of the lesions reflect their structural heterogeneity and correlate with local variations in mineral content, tissue age, and remodeling rates, in the same way as normal bone. © 2018 American Society for Bone and Mineral Research

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“…Src-activation is regulated by a number of different signals, including VEGF-A receptor actions. An increase in Src phosphorylation during the acute phase of ischemia is associated with VEGF-induced vascular permeability [ 33 , 88 , 89 ]. Src activation then returns to basal levels within the first day, before a second increase occurs 3–7 days after reperfusion [ 33 ].…”

Section: Vegf-a In the Prevention And Therapy Of Strokementioning

confidence: 99%

The Janus Face of VEGF in Stroke

Geiseler

Morland

2018

IJMS

135

124

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The family of vascular endothelial growth factors (VEGFs) are known for their regulation of vascularization. In the brain, VEGFs are important regulators of angiogenesis, neuroprotection and neurogenesis. Dysregulation of VEGFs is involved in a large number of neurodegenerative diseases and acute neurological insults, including stroke. Stroke is the main cause of acquired disabilities, and normally results from an occlusion of a cerebral artery or a hemorrhage, both leading to focal ischemia. Neurons in the ischemic core rapidly undergo necrosis. Cells in the penumbra are exposed to ischemia, but may be rescued if adequate perfusion is restored in time. The neuroprotective and angiogenic effects of VEGFs would theoretically make VEGFs ideal candidates for drug therapy in stroke. However, contradictory to what one might expect, endogenously upregulated levels of VEGF as well as the administration of exogenous VEGF is detrimental in acute stroke. This is probably due to VEGF-mediated blood–brain-barrier breakdown and vascular leakage, leading to edema and increased intracranial pressure as well as neuroinflammation. The key to understanding this Janus face of VEGF function in stroke may lie in the timing; the harmful effect of VEGFs on vessel integrity is transient, as both VEGF preconditioning and increased VEGF after the acute phase has a neuroprotective effect. The present review discusses the multifaceted action of VEGFs in stroke prevention and therapy.

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Src inhibitor reduces permeability without disturbing vascularization and prevents bone destruction in steroid-associated osteonecrotic lesions in rabbits

Cited by 6 publications

References 48 publications

Modulation of long‐term endothelial‐barrier integrity is conditional to the cross‐talk between Akt and Src signaling

Modulation of long‐term endothelial‐barrier integrity is conditional to the cross‐talk between Akt and Src signaling

Melorheostotic Bone Lesions Caused by Somatic Mutations in MAP2K1 Have Deteriorated Microarchitecture and Periosteal Reaction

The Janus Face of VEGF in Stroke

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