Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species

Wang, Youxue; Zang, Qun S.; Liu, Zijuan; Qian, Wei; Maass, David L.; Dulan, Genevieve; Shaul, Philip W.; Melito, Lisa; Frantz, Doug E.; Kilgore, Jessica A.; Williams, Noelle S.; Terada, Lance S.; Nwariaku, Fiemu E.

doi:10.1152/ajpcell.00322.2010

Cited by 158 publications

(118 citation statements)

References 52 publications

(63 reference statements)

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“…23 However, a few in vitro studies directly indicated ROS as a Rac1 activator, 24,25 similar to our observations. In addition, Wang et al 26 indirectly showed that vascular endothelial growth factor-evoked mitochondrial ROS activated Rac1 and induced cell migration in endothelial cells. Mitochondrial delivery of vitamin E or overexpression of mitochondrial catalase blocked Rac1 activation and suppressed vascular endothelial growth factor-stimulated endothelial cell migration, which was reversed by CARac1.…”

Section: Discussionmentioning

confidence: 99%

Oxidative Stress Causes Mineralocorticoid Receptor Activation in Rat Cardiomyocytes

et al. 2012

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Abstract-Overactivation of the mineralocorticoid receptor signaling is implicated in cardiovascular disease, including hypertensive heart disease. Oxidative stress is suggested to augment mineralocorticoid receptor signal transduction, but the precise mechanisms remain unclear. Mineralocorticoid receptor activity is regulated by multiple factors, in addition to plasma ligand levels. We previously identified Rac1 GTPase as a modulator of mineralocorticoid receptor activity.Here we show that oxidative stress induces mineralocorticoid receptor activation in a ligand-independent, Rac1-depenent manner in cardiomyocytes. Oxidant stress was induced in rat cultured cardiomyocytes (H9c2) by L-buthionine sulfoximine (BSO), an inhibitor of glutathione synthesis. BSO depleted intracellular glutathione and concomitantly increased reactive oxygen species (199%; PϽ0.01). BSO significantly enhanced the corticosterone-induced, mineralocorticoid receptor-dependent luciferase reporter activity (186%; PϽ0.01) and basal luciferase activity without ligand stimulation. These effects were inhibited by the antioxidant N-acetylcysteine. The ligand independency of BSO action was indicated using a mutant mineralocorticoid receptor that does not bind ligands. With this mutant mineralocorticoid receptor, BSO-evoked mineralocorticoid receptor activation remained intact, whereas ligand-induced mineralocorticoid receptor activation was abolished. We next examined the involvement of Rac1. BSO increased active Rac1 in a redox-dependent fashion, and Rac inhibition suppressed the enhancing effect of BSO. Constitutively active Rac1, indeed, potentiated mineralocorticoid receptor transactivation. Furthermore, mineralocorticoid receptor transactivation by BSO was accompanied by enhanced nuclear accumulation of mineralocorticoid receptor. We conclude that alteration of redox state modulates mineralocorticoid receptor-dependent transcriptional activity via Rac1 in the heart. This redox-sensitive, ligand-independent mineralocorticoid receptor activation may contribute to the processes by which oxidant stress promotes cardiac injury. (Hypertension. 2012;59[part 2]:500-506.)

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Section: Discussionmentioning

confidence: 99%

Oxidative Stress Causes Mineralocorticoid Receptor Activation in Rat Cardiomyocytes

et al. 2012

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“…The cytoplasmic and mitochondrial ROS pathways are tightly intertwined (Dikalov et al, 2014;Nazarewicz et al, 2013), and mediate shear-stress-induced blood vessel dilation, vascular permeability and angiogenesis (Liu et al, 2003;Pearlstein et al, 2002). In addition, low levels of ROS are known to induce angiogenesis partly through upregulation of VEGF and activation of VEGFR2 signaling (Chua et al, 1998;Wang et al, 2011b).…”

Section: Oxidative Phosphorylation In Mitochondriamentioning

confidence: 99%

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

Stapor

Wang

Goveia

et al. 2014

Journal of Cell Science

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Clinically approved therapies that target angiogenesis in tumors and ocular diseases focus on controlling pro-angiogenic growth factors in order to reduce aberrant microvascular growth. Although research on angiogenesis has revealed key mechanisms that regulate tissue vascularization, therapeutic success has been limited owing to insufficient efficacy, refractoriness and tumor resistance. Emerging concepts suggest that, in addition to growth factors, vascular metabolism also regulates angiogenesis and is a viable target for manipulating the microvasculature. Recent studies show that endothelial cells rely on glycolysis for ATP production, and that the key glycolytic regulator 6-phosphofructo-2-kinase/ fructose-2,6-bisphosphatase 3 (PFKFB3) regulates angiogenesis by controlling the balance of tip versus stalk cells. As endothelial cells acquire a tip cell phenotype, they increase glycolytic production of ATP for sprouting. Furthermore, pharmacological blockade of PFKFB3 causes a transient, partial reduction in glycolysis, and reduces pathological angiogenesis with minimal systemic harm. Although further assessment of endothelial cell metabolism is necessary, these results represent a paradigm shift in anti-angiogenic therapy from targeting angiogenic factors to focusing on vascular metabolism, warranting research on the metabolic pathways that govern angiogenesis.

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“…Mitochondrial ROS formation has been associated with impairment of cell migration 12 . As shown in Figure 3 exposure of EEC to chlorambucil resulted in the breakdown of mitochondrial membrane potential 9 .…”

Section: Representative Resultsmentioning

confidence: 99%

Assessment of Endothelial Cell Migration After Exposure to Toxic Chemicals

Steinritz

Schmidt

Balszuweit

et al. 2015

JoVE

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Exposure to chemical substances (including alkylating chemical warfare agents like sulfur and nitrogen mustards) cause a plethora of clinical symptoms including wound healing disorder. The physiological process of wound healing is highly complex. The formation of granulation tissue is a key step in this process resulting in a preliminary wound closure and providing a network of new capillary blood vessels -either through vasculogenesis (novel formation) or angiogenesis (sprouting of existing vessels). Both vasculo-and angiogenesis require functional, directed migration of endothelial cells. Thus, investigation of early endothelial cell (EEC) migration is important to understand the pathophysiology of chemical induced wound healing disorders and to potentially identify novel strategies for therapeutic intervention.We assessed impaired wound healing after alkylating agent exposure and tested potential candidate compounds for treatment. We used a set of techniques outlined in this protocol. A modified Boyden chamber to quantitatively investigate chemokinesis of EEC is described. Moreover, the use of the wound healing assay in combination with track analysis to qualitatively assess migration is illustrated. Finally, we demonstrate the use of the fluorescent dye TMRM for the investigation of mitochondrial membrane potential to identify underlying mechanisms of disturbed cell migration. The following protocol describes basic techniques that have been adapted for the investigation of EEC. Video LinkThe video component of this article can be found at

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Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species

Abstract: NS, Terada LS, Nwariaku FE. Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species.

Cited by 158 publications

References 52 publications

Oxidative Stress Causes Mineralocorticoid Receptor Activation in Rat Cardiomyocytes

Oxidative Stress Causes Mineralocorticoid Receptor Activation in Rat Cardiomyocytes

Angiogenesis revisited – role and therapeutic potential of targeting endothelial metabolism

Assessment of Endothelial Cell Migration After Exposure to Toxic Chemicals

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