Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease

Satyanarayana Alleboina; Dawit Ayalew; Rahul Peravali; Lingdan Chen; Thomas Wong; Ayotunde O Dokun

doi:10.1177/1358863X19866254

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Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease

Journal article

Open access

Peer reviewed

Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease

Satyanarayana Alleboina, Dawit Ayalew, Rahul Peravali, Lingdan Chen, Thomas Wong and Ayotunde O Dokun

Vascular medicine (London, England), Vol.24(5), pp.395-404

10/2019

DOI: 10.1177/1358863X19866254

PMCID: PMC7664318

PMID: 31451089

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Abstract

Peripheral artery disease (PAD) is caused by atherosclerotic occlusions of vessels outside the heart, particularly those of the lower extremities. Angiogenesis is one critical physiological response to vessel occlusion in PAD, but our understanding of the molecular mechanisms involved in angiogenesis is incomplete. Dual specificity phosphatase 5 (DUSP5) has been shown to play a key role in embryonic vascular development, but its role in post-ischemic angiogenesis is not known. We induced hind limb ischemia in mice and found robust upregulation of Dusp5 expression in ischemic hind limbs. Moreover, in vivo knockdown of Dusp5 resulted in impaired perfusion recovery in ischemic limbs and was associated with increased limb necrosis. In vitro studies showed upregulation of DUSP5 in human endothelial cells exposed to ischemia, and knockdown of DUSP5 in these ischemic endothelial cells resulted in impaired endothelial cell proliferation and angiogenesis, but did not alter apoptosis. Finally, we show that these effects of DUSP5 on post-ischemic angiogenesis are a result of DUSP5-dependent decrease in ERK1/2 phosphorylation and p21 protein expression. Thus, we have identified a role of DUSP5 in post-ischemic angiogenesis and implicated a DUSP5-ERK-p21 pathway that may serve as a therapeutic target for the modulation of post-ischemic angiogenesis in PAD.

Animals

Cell Line

Cell Proliferation

Cyclin-Dependent Kinase Inhibitor p21 - metabolism

Disease Models, Animal

Dual-Specificity Phosphatases - genetics

Dual-Specificity Phosphatases - metabolism

Extracellular Signal-Regulated MAP Kinases - metabolism

Gene Knockdown Techniques

Hindlimb - blood supply

Human Umbilical Vein Endothelial Cells - enzymology

Human Umbilical Vein Endothelial Cells - pathology

Humans

Ischemia - enzymology

Ischemia - genetics

Ischemia - physiopathology

Male

Mice, Inbred C57BL

Neovascularization, Physiologic

Peripheral Arterial Disease - enzymology

Peripheral Arterial Disease - genetics

Peripheral Arterial Disease - physiopathology

Phosphorylation

Recovery of Function

Regional Blood Flow

Signal Transduction

Details

Title: Subtitle: Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease
Creators: Satyanarayana Alleboina - Division of Endocrinology, Diabetes and Metabolism, Health Sciences Center, University of Tennessee, Memphis, TN, USA
Dawit Ayalew - University of Virginia
Rahul Peravali - Division of Endocrinology, Diabetes and Metabolism, Health Sciences Center, University of Tennessee, Memphis, TN, USA
Lingdan Chen - University of Virginia
Thomas Wong - University of Iowa
Ayotunde O Dokun - University of Iowa
Resource Type: Journal article
Publication Details: Vascular medicine (London, England), Vol.24(5), pp.395-404
DOI: 10.1177/1358863X19866254
PMID: 31451089
PMCID: PMC7664318
NLM abbreviation: Vasc Med
ISSN: 1358-863X
eISSN: 1477-0377
Grant note: R01 HL130399 / NHLBI NIH HHS
Language: English
Date published: 10/2019
Academic Unit: Molecular Physiology and Biophysics; Fraternal Order of Eagles Diabetes Research Center; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984297613102771

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