Dataset Information

Endothelial Cell Autonomous Role of Akt1: Regulation of Vascular Tone and Ischemia-Induced Arteriogenesis.

ABSTRACT:

Objective

The importance of PI3K/Akt signaling in the vasculature has been demonstrated in several models, as global loss of Akt1 results in impaired postnatal ischemia- and VEGF-induced angiogenesis. The ubiquitous expression of Akt1, however, raises the possibility of cell-type-dependent Akt1-driven actions, thereby necessitating tissue-specific characterization.

Approach and results

Herein, we used an inducible, endothelial-specific Akt1-deleted adult mouse model (Akt1iECKO) to characterize the endothelial cell autonomous functions of Akt1 in the vascular system. Endothelial-targeted ablation of Akt1 reduces eNOS (endothelial nitric oxide synthase) phosphorylation and promotes both increased vascular contractility in isolated vessels and elevated diastolic blood pressures throughout the diurnal cycle in vivo. Furthermore, Akt1iECKO mice subject to the hindlimb ischemia model display impaired blood flow and decreased arteriogenesis.

Conclusions

Endothelial Akt1 signaling is necessary for ischemic resolution post-injury and likely reflects the consequence of NO insufficiency critical for vascular repair.

SUBMITTER: Lee MY

PROVIDER: S-EPMC6503971 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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Publications

Endothelial Cell Autonomous Role of Akt1: Regulation of Vascular Tone and Ischemia-Induced Arteriogenesis.

Lee Monica Y MY Gamez-Mendez Ana A Zhang Jiasheng J Zhuang Zhenwu Z Vinyard David J DJ Kraehling Jan J Velazquez Heino H Brudvig Gary W GW Kyriakides Themis R TR Simons Michael M Sessa William C WC

Arteriosclerosis, thrombosis, and vascular biology 20180215 4

<h4>Objective</h4>The importance of PI3K/Akt signaling in the vasculature has been demonstrated in several models, as global loss of Akt1 results in impaired postnatal ischemia- and VEGF-induced angiogenesis. The ubiquitous expression of Akt1, however, raises the possibility of cell-type-dependent Akt1-driven actions, thereby necessitating tissue-specific characterization.<h4>Approach and results</h4>Herein, we used an inducible, endothelial-specific Akt1-deleted adult mouse model (Akt1iECKO) to ...[more]

PMID: 29449333

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Project description:Cerebral vascular endothelial cell (CEC) degeneration significantly contributes to blood-brain barrier (BBB) breakdown and neuronal loss after cerebral ischemia. Recently, emerging data suggest that peroxisome proliferator-activated receptor delta (PPARdelta) activation has a potential neuroprotective role in ischemic stroke. Here we report for the first time that PPARdelta is significantly reduced in oxygen-glucose deprivation (OGD)-induced mouse CEC death. Interestingly, PPARdelta overexpression can suppress OGD-induced caspase-3 activity, Golgi fragmentation, and CEC death through an increase of bcl-2 protein levels without change of bcl-2 mRNA levels. To explore the molecular mechanisms, we have identified that upregulation of PPARdelta can alleviate ODG-activated microRNA-15a (miR-15a) expression in CECs. Moreover, we have demonstrated that bcl-2 is a translationally repressed target of miR-15a. Intriguingly, gain- or loss-of-miR-15a function can significantly reduce or increase OGD-induced CEC death, respectively. Furthermore, we have identified that miR-15a is a transcriptional target of PPARdelta. Consistent with the in vitro findings, we found that intracerebroventricular infusion of a specific PPARdelta agonist, GW 501516 (2-[2-methyl-4-[[4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl]methylsulfanyl]phenoxy]acetic acid), significantly reduced ischemia-induced miR-15a expression, increased bcl-2 protein levels, and attenuated caspase-3 activity and subsequent DNA fragmentation in isolated cerebral microvessels, leading to decreased BBB disruption and reduced cerebral infarction in mice after transient focal cerebral ischemia. Together, these results suggest that PPARdelta plays a vascular-protective role in ischemia-like insults via transcriptional repression of miR-15a, resulting in subsequent release of its posttranscriptional inhibition of bcl-2. Thus, regulation of PPARdelta-mediated miR-15a inhibition of bcl-2 could provide a novel therapeutic strategy for the treatment of stroke-related vascular dysfunction.

Project description:ObjectiveThioredoxin-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 resultsIn 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.ConclusionsThese 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.

Dataset Information

Endothelial Cell Autonomous Role of Akt1: Regulation of Vascular Tone and Ischemia-Induced Arteriogenesis.

Objective

Approach and results

Conclusions

Publications

Endothelial Cell Autonomous Role of Akt1: Regulation of Vascular Tone and Ischemia-Induced Arteriogenesis.

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