Regulation of smooth muscle cell migration and integrin expression by the Gax transcription factor

Witzenbichler, Bernhard; Kureishi, Yasuko; Luo, Zhengyu; Roux, Aude Le; Branellec, Didier; Walsh, Kenneth

doi:10.1172/jci7251

Cited by 79 publications

(62 citation statements)

References 75 publications

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“…Migration Assay-Migration assays were performed as described previously using a modified Boyden chamber (Neuroprobe, Cabin John, MD) (36). HUVECs infected with the indicated adenoviral vectors were serum-starved overnight in serum-free media (EBM).…”

Section: Methodsmentioning

confidence: 99%

AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

Nagata¹,

Mogi

Walsh

2003

Journal of Biological Chemistry

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322

338

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AMP-activated protein kinase (AMPK) is a stress-activated protein kinase that is regulated by hypoxia and other cellular stresses that result in diminished cellular ATP levels. Here, we investigated whether AMPK signaling in endothelial cells has a role in regulating angiogenesis. Hypoxia induced the activating phosphorylation of AMPK in human umbilical vein endothelial cells (HUVECs), and AMPK activation was required for the maintenance of pro-angiogenic Akt signaling under these conditions. Suppression of AMPK signaling inhibited both HUVEC migration to VEGF and in vitro differentiation into tube-like structures in hypoxic, but not normoxic cultures. Dominant-negative AMPK also inhibited in vivo angiogenesis in Matrigel plugs that were implanted subcutaneously in mice. These data identify AMPK signaling as a new regulator of angiogenesis that is specifically required for endothelial cell migration and differentiation under conditions of hypoxia. As such, endothelial AMPK signaling may be a critical determinant of blood vessel recruitment to tissues that are subjected to ischemic stress.Angiogenesis is central feature of normal embryonic and post-natal development, and this process plays a critical role in the neovascularization that is associated with tumor growth and occlusive vascular diseases (1-3). A large body of evidence has shown that vascular angiogenic growth factors promote angiogenesis through activation of MAP kinase (4) and phosphatidylinositol 3-kinase (PI3K)-Akt/PKB (5) intracellular signaling pathways. However, the signaling molecules involved in angiogenic cellular responses under conditions of hypoxic stress is incompletely understood.AMP-activated protein kinase (AMPK) 1 is a metabolite-sensing protein kinase that shares amino acid sequence homology with yeast SNF1 (6, 7). In myocytes, AMPK is activated by increases in the AMP:ATP ratio, which is brought about by hypoxia/anoxia (8 -10), vigorous exercise and muscle contraction (11-14) or pressure-overload hypertrophy (15). Under these conditions, AMPK is activated by a conformational change after binding AMP (16,17), and by phosphorylation by its upstream kinase AMPK kinase (AMPKK) (17-19). Upon activation, AMPK phosphorylates and down-regulates several anabolic enzymes including 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (16,20), acetyl-CoA carboxylase (ACC) (16, 21), sn-glycerol-3-phosphate acetyltransferase (22, 23), and glycogen synthase (24); thereby diminishing metabolite flux through synthetic pathways that consume ATP. AMPK activation also accelerates ␤-oxidation of fatty acid, which promotes ATP production (25, 26).Endothelial nitric-oxide synthase (eNOS) residue 1177 (in human) is a substrate for both Akt (27, 28) and AMPK (29). Phosphorylation of eNOS at this residue leads to enzyme activation and nitric oxide (NO) production. AMPK is reported to phosphorylate eNOS in cardiac myocytes under hypoxic conditions (29), but it is not clear whether NO production by endothelial cells is regulated by this reaction. Recently, AMPK ...

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Section: Methodsmentioning

confidence: 99%

AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

Nagata¹,

Mogi

Walsh

2003

Journal of Biological Chemistry

Self Cite

322

338

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“…17 Gax also controls the migration of VSMCs toward chemotactic growth factors, an effect that can be correlated with its ability to downregulate expression of integrins ␣ V ␤ 3 and ␣ V ␤ 5 both in vitro and in vivo, which are induced in synthetic state VSMCs. 18 Thus, a model of homeobox gene action in VSMCs can be postulated from these observations, in which a subset of homeobox genes, such as Hex and HOXB7, promotes the synthetic phenotype and another subset, containing Gax, tends to promote a more quiescent, contractile phenotype.…”

mentioning

confidence: 99%

Control of Vascular Cell Differentiation by Homeobox Transcription Factors

Gorski¹

2003

Trends in Cardiovascular Medicine

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“…20 However, homeodomain transcription factors are widely recognized to function as pleiotropic regulators and gax overexpression may also affect VSMC differentiation, migration or viability. 22,61,62 In contrast to the Ad-Gaxtreated arteries, no discernible difference was seen in the extent of neointima formation between the Ad-CMVluctreated and saline-treated arteries in the control group of animals. The ability of Gax overexpression to inhibit neointima formation compares favorably with previous recent results reported by other groups using adenovirusencoded genes for wild-type and mutant form of RB in rat and porcine models, 46,63 the herpes simplex virus thymidine kinase gene in rat, rabbit and porcine models, 26,27,55,56 p21 53 in the rat model and hirudin in the rat model.…”

Section: Enzymes Withmentioning

confidence: 81%

“…Other homeobox genes have been shown to function as regulators of cellular differentiation and growth, 7,8 we have shown that overexpression of the Gax gene in normal rat carotid and rabbit iliac arteries can inhibit the fibro-proliferative response to balloon injury, 20,21 an effect that may be mediated by its ability to suppress integrin expression. 22 Adenovirus-mediated gene transfer performed in atheromatous vessels [23][24][25][26][27] combined with stent implantation [28][29][30][31][32][33][34] constitute two important challenges for clinical application. Here, we present the results of percutaneous adenovirus-mediated Gax gene transfer to atheromatous, stented rabbit iliac arteries in a clinical model of balloon angioplasty performed with the channel balloon catheter.…”

Section: Introductionmentioning

confidence: 99%

Effect of percutaneous adenovirus-mediated Gax gene delivery to the arterial wall in double-injured atheromatous stented rabbit iliac arteries

et al. 2000

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Though the efficacy of intravascular gene transfer has been demonstrated in native vessels following acute injury, this methodology has not been validated in complex models of vascular injury that more closely mimic clinical angioplasty procedures. Previous studies have shown that Gax gene overexpression modulates the injury-induced remodeling of the vessel in rat carotid and normal rabbit iliac arteries. Here, we evaluated the effect of the Gax gene delivery in atheromatous stented vessels. Rabbits were fed 120 g daily of 1% cholesterol diet for 3 weeks. At 1 week they underwent initial injury on the external iliac artery, then balloon angioplasty was performed at 3 weeks at the same site with a 2.5 mm diameter channel balloon catheter (three times 1 min at 6 atm). Either saline (n = 4) or the control viral construct Ad-CMVluc (5 × 10 9 p.f.u.) (n = 5) or Ad-CMVGax (5 × 10 9 p.f.u.) (n = 4) was delivered with a poloxamer mixture via a channel balloon (6 atm, 30 min), and a 15 mm long

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Regulation of smooth muscle cell migration and integrin expression by the Gax transcription factor

Cited by 79 publications

References 75 publications

AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

AMP-activated Protein Kinase (AMPK) Signaling in Endothelial Cells Is Essential for Angiogenesis in Response to Hypoxic Stress

Control of Vascular Cell Differentiation by Homeobox Transcription Factors

Effect of percutaneous adenovirus-mediated Gax gene delivery to the arterial wall in double-injured atheromatous stented rabbit iliac arteries

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