Endothelial-Specific Expression of Mitochondrial Thioredoxin Promotes Ischemia-Mediated Arteriogenesis and Angiogenesis
- 1 April 2009
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Arteriosclerosis, Thrombosis, and Vascular Biology
- Vol. 29 (4), 495-502
- https://doi.org/10.1161/atvbaha.108.180349
Abstract
Objective— Thioredoxin-2 (Trx2), a major antioxidant protein in mitochondria, enhances nitric oxide bioavailability and inhibits ASK1-dependent apoptosis in endothelial cells (ECs). However, the in vivo role of Trx2 in angiogenesis has not been defined. Here we used EC-specific transgenesis of Trx2 (Trx2-TG) in mice to determine the in vivo function of Trx2 in arteriogenesis and angiogenesis. Methods and Results— In a femoral artery ligation model, Trx2-TG mice had enhanced capacity in limb perfusion recovery and ischemic reserve capacity compared to the nontransgenic littermates. Ischemia-initiated arteriogenesis in the upper limb was augmented in Trx2-TG mice. Trx2-TG mice also showed significantly enhanced capillary formation and maturation in the lower limb. In nontransgenic limb, ischemia specifically induced a downregulation of Trx2 protein, leading to increased oxidative stress, ASK1 activation, and EC apoptosis. In contrast, Trx2-TG maintained a constitutive level of Trx2, reducing the ischemia-induced deleterious responses. We then defined the mechanism by which Trx2 increases angiogenesis using ECs isolated from Trx2-TG mice. Trx2-TG ECs showed increased NO and NO-dependent migration. In addition, these cells were more resistant to oxidative stress–induced activation of ASK1 signaling and apoptosis. Moreover, Trx2-augmented EC survival is NO-independent. To define the relative contributions of Trx2-increased NO and Trx2-reduced ASK1 apoptotic activity to angiogenesis in vivo, we examined Trx2 effects on ischemia-induced angiogenesis in eNOS-deficient mice. The eNOS deletion caused severe impairment in the functional flow recovery in response to ischemia. Trx2 expression in eNOS-KO mice still dramatically inhibited ischemia-induced ASK1 and EC apoptosis, leading to an enhanced functional flow recovery. Conclusion— These in vivo and in vitro data support that Trx2 maintains EC function by two parallel pathways—scavenging ROS to increase NO bioavailability and inhibiting ASK1 activity to enhance EC survival, facilitating ischemia-mediated arteriogenesis and angiogenesis.Keywords
This publication has 34 references indexed in Scilit:
- Mitochondrial H2O2 Regulates the Angiogenic Phenotype via PTEN OxidationPublished by Elsevier BV ,2005
- Angiogenesis in health and diseaseNature Medicine, 2003
- The Absence of Mitochondrial Thioredoxin 2 Causes Massive Apoptosis, Exencephaly, and Early Embryonic Lethality in Homozygous MiceMolecular and Cellular Biology, 2003
- Mitochondria, nitric oxide, and cardiovascular dysfunctionFree Radical Biology & Medicine, 2002
- Redox regulatory and anti-apoptotic functions of thioredoxin depend on S-nitrosylation at cysteine 69Nature, 2002
- Mitochondrial Integrity and Function in AtherogenesisCirculation, 2002
- Thioredoxin Promotes ASK1 Ubiquitination and Degradation to Inhibit ASK1-Mediated Apoptosis in a Redox Activity-Independent MannerCirculation Research, 2002
- Overexpression of Endothelial Nitric Oxide Synthase in Endothelial Cells Is Protective against Ischemia-Reperfusion Injury in Mouse Skeletal MuscleThe American Journal of Pathology, 2002
- Thioredoxin-2 (TRX-2) is an essential gene regulating mitochondria-dependent apoptosisThe EMBO Journal, 2002
- Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damageNature, 2000