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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalVascular Medicine (United Kingdom)
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Dual-Specificity Phosphatases
Peripheral Arterial Disease
Perfusion
Extremities
Endothelial Cells
Up-Regulation
Ischemia
MAP Kinase Signaling System
Embryonic Development
Blood Vessels
Lower Extremity
Necrosis
Phosphorylation
Cell Proliferation
Apoptosis

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease. / Alleboina, Satyanarayana; Ayalew, Dawit; Peravali, Rahul; Chen, Lingdan; Wong, Thomas; Dokun, Ayotunde.

In: Vascular Medicine (United Kingdom), 01.01.2019.

Research output: Contribution to journalArticle

Alleboina, Satyanarayana ; Ayalew, Dawit ; Peravali, Rahul ; Chen, Lingdan ; Wong, Thomas ; Dokun, Ayotunde. / Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease. In: Vascular Medicine (United Kingdom). 2019.
@article{46c3dba00a7443b69adb703b680bf69b,
title = "Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease",
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.",
author = "Satyanarayana Alleboina and Dawit Ayalew and Rahul Peravali and Lingdan Chen and Thomas Wong and Ayotunde Dokun",
year = "2019",
month = "1",
day = "1",
doi = "10.1177/1358863X19866254",
language = "English (US)",
journal = "Vascular Medicine",
issn = "1358-863X",
publisher = "SAGE Publications Ltd",

}

TY - JOUR

T1 - Dual specificity phosphatase 5 regulates perfusion recovery in experimental peripheral artery disease

AU - Alleboina, Satyanarayana

AU - Ayalew, Dawit

AU - Peravali, Rahul

AU - Chen, Lingdan

AU - Wong, Thomas

AU - Dokun, Ayotunde

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85071665806&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85071665806&partnerID=8YFLogxK

U2 - 10.1177/1358863X19866254

DO - 10.1177/1358863X19866254

M3 - Article

JO - Vascular Medicine

JF - Vascular Medicine

SN - 1358-863X

ER -