Endothelial Nuclear Factor-κB–Dependent Regulation of Arteriogenesis and Branching

Tı̂rziu, Daniela; Jaba, Irina M.; Yu, Pengchun; Larrivée, Bruno; Coon, Brian G.; Cristofaro, Brunella; Zhuang, Zhen W.; Lanahan, Anthony A.; Schwartz, Martin A.; Eichmann, Anne; Simons, Michael

doi:10.1161/circulationaha.112.119321

Cited by 62 publications

(82 citation statements)

References 49 publications

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“…We observed a significant increase in p65 phosphorylation (subunit of NF-κB) in the retina, along with an increase in VEGFA and HIF-1A gene expression. Accordingly, an acute hypoxic episode triggers NF-κB activation in retinal cells in vitro and in vivo (18,27) and HIF-1A mRNA accumulates in rat brain in response to hypoxia (28). Since NF-kB activation is a common event that links several stress and survival signaling pathways (29), we propose that NF-κB might be a key regulator of the retinal stress response after hypoxia.…”

Section: Articlesmentioning

confidence: 91%

Metabolic adaptation and neuroprotection differ in the retina and choroid in a piglet model of acute postnatal hypoxia

et al. 2014

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Background: Hypoxic-ischemic insults to the neonatal brain may cause neurodevelopmental disorders. Vulnerability of different areas of the neural tissue to hypoxic-ischemic stress might be explained by either heterogeneous sensitivity to oxygen or neuroprotective capability. Our understanding of regional heterogeneity is still incomplete in terms of metabolic reconfiguration and/or activation of neuroprotective mechanisms. Methods: We studied, by western blotting, reversetranscriptase PCR, and tandem mass spectrometry, the response of retina and choroid at protein, gene, and metabolic levels during hypoxia in a piglet model of acute postnatal hypoxia. results: We evidenced a metabolic shift towards glycolysis in choroid after hypoxia while retina experienced a dramatic energy stress with decreased mitochondrial metabolites. Hypoxia-inducible transcription factor-1α (HIF-1α) was not stabilized in retina during hypoxia, supported by a deficient signaling from v-akt murine thymoma viral oncogene (AKT) and ERK1/2, and unchanged glutathione redox status. In retina, but not in choroid, phosphorylation of p65 (NF-κB) and increased transcription of target genes may have a major role during hypoxic stress. conclusion: We showed that the retina engages a distinct pattern of signaling and transcriptional events than observed in the choroid. Retina and choroid may reflect regional sensitivity to hypoxia. While prolonged and intense hypoxia may jeopardize retinal cell survival, choroid sets up a different pattern of response, which promotes adaptation to these adverse conditions.

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Section: Articlesmentioning

confidence: 91%

Metabolic adaptation and neuroprotection differ in the retina and choroid in a piglet model of acute postnatal hypoxia

et al. 2014

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“…In addition to Hif2a, inducible blockade of NFκB in endothelial cells using a transgenic mouse line overexpressing IκB also leads to reduction in Dll4 levels, retinal hypervascularization and reduced post-ischemic blood flow recovery. Activation of Notch signaling via administration of Jag1 peptide rescues a normal vascular phenotype, indicating that NFκkB signaling, which is controlled by shear stress, regulates arterial branching morphogenesis via induction of Dll4-Notch signaling (Tirziu et al, 2012).…”

Section: Efnb2 Is Upregulated In Dll4mentioning

confidence: 99%

Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models

et al. 2013

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SUMMARYArteriogenesis requires growth of pre-existing arteriolar collateral networks and determines clinical outcome in arterial occlusive diseases. Factors responsible for the development of arteriolar collateral networks are poorly understood. The Notch ligand Deltalike 4 (Dll4) promotes arterial differentiation and restricts vessel branching. We hypothesized that Dll4 may act as a genetic determinant of collateral arterial networks and functional recovery in stroke and hind limb ischemia models in mice. Genetic lossand gain-of-function approaches in mice showed that Dll4-Notch signaling restricts pial collateral artery formation by modulating arterial branching morphogenesis during embryogenesis. Adult Dll4 +/− mice showed increased pial collateral numbers, but stroke volume upon middle cerebral artery occlusion was not reduced compared with wild-type littermates. Likewise, Dll4 +/− mice showed reduced blood flow conductance after femoral artery occlusion, and, despite markedly increased angiogenesis, tissue ischemia was more severe. In peripheral arteries, loss of Dll4 adversely affected excitation-contraction coupling in arterial smooth muscle in response to vasopressor agents and arterial vessel wall adaption in response to increases in blood flow, collectively contributing to reduced flow reserve. We conclude that Dll4-Notch signaling modulates native collateral formation by acting on vascular branching morphogenesis during embryogenesis. Dll4 furthermore affects tissue perfusion by acting on arterial function and structure. Loss of Dll4 stimulates collateral formation and angiogenesis, but in the context of ischemic diseases such beneficial effects are overruled by adverse functional changes, demonstrating that ischemic recovery is not solely determined by collateral number but rather by vessel functionality.

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“…7). On the other hand, inhibition of NFkB signalling, impairing VEGF-A and platelet-derived growth factor-B expression, led to a hyperbranched and immature collateral network 8 . Thus, an increase in stable and regulated microvessels is required to induce functional neovascularization.…”

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confidence: 99%

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

et al. 2014

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Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin 4 (T 4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or T 4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the T 4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as T 4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing T 4 (T 4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.

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Endothelial Nuclear Factor-κB–Dependent Regulation of Arteriogenesis and Branching

Cited by 62 publications

References 49 publications

Metabolic adaptation and neuroprotection differ in the retina and choroid in a piglet model of acute postnatal hypoxia

Metabolic adaptation and neuroprotection differ in the retina and choroid in a piglet model of acute postnatal hypoxia

Dll4-Notch signaling determines the formation of native arterial collateral networks and arterial function in mouse ischemia models

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

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