Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential

Richard M. Cubbon, Nadira Y. Yuldasheva, Hema Viswambharan, Ben N. Mercer, Vivek Baliga, Sam L. Stephen, Jonathan Askham, Piruthivi Sukumar, Anna Skromna, Romana S. Mughal, Andrew M.N. Walker, Alexander Bruns, Marc A. Bailey, Stacey Galloway, Helen Imrie, Matthew C. Gage, Mark Rakobowchuk, Jing Li, Karen E. Porter, Sreenivasan Ponnambalam & 3 others Stephen B. Wheatcroft, David J. Beech, Mark T. Kearney

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Abstract

Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.

LanguageEnglish
Pages2714-2723
Number of pages10
JournalStem Cells
Volume32
Issue number10
DOIs
Publication statusPublished - 15 Sep 2014
Externally publishedYes

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Blood Vessels
Endothelial Cells
Nitric Oxide Synthase Type III
Femoral Artery
Extremities
Green Fluorescent Proteins
Ischemia
Perfusion

Cite this

Cubbon, R. M., Yuldasheva, N. Y., Viswambharan, H., Mercer, B. N., Baliga, V., Stephen, S. L., ... Kearney, M. T. (2014). Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential. Stem Cells, 32(10), 2714-2723. https://doi.org/10.1002/stem.1766
Cubbon, Richard M. ; Yuldasheva, Nadira Y. ; Viswambharan, Hema ; Mercer, Ben N. ; Baliga, Vivek ; Stephen, Sam L. ; Askham, Jonathan ; Sukumar, Piruthivi ; Skromna, Anna ; Mughal, Romana S. ; Walker, Andrew M.N. ; Bruns, Alexander ; Bailey, Marc A. ; Galloway, Stacey ; Imrie, Helen ; Gage, Matthew C. ; Rakobowchuk, Mark ; Li, Jing ; Porter, Karen E. ; Ponnambalam, Sreenivasan ; Wheatcroft, Stephen B. ; Beech, David J. ; Kearney, Mark T. / Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential. In: Stem Cells. 2014 ; Vol. 32, No. 10. pp. 2714-2723.
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abstract = "Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.",
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Cubbon, RM, Yuldasheva, NY, Viswambharan, H, Mercer, BN, Baliga, V, Stephen, SL, Askham, J, Sukumar, P, Skromna, A, Mughal, RS, Walker, AMN, Bruns, A, Bailey, MA, Galloway, S, Imrie, H, Gage, MC, Rakobowchuk, M, Li, J, Porter, KE, Ponnambalam, S, Wheatcroft, SB, Beech, DJ & Kearney, MT 2014, 'Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential', Stem Cells, vol. 32, no. 10, pp. 2714-2723. https://doi.org/10.1002/stem.1766

Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential. / Cubbon, Richard M.; Yuldasheva, Nadira Y.; Viswambharan, Hema; Mercer, Ben N.; Baliga, Vivek; Stephen, Sam L.; Askham, Jonathan; Sukumar, Piruthivi; Skromna, Anna; Mughal, Romana S.; Walker, Andrew M.N.; Bruns, Alexander; Bailey, Marc A.; Galloway, Stacey; Imrie, Helen; Gage, Matthew C.; Rakobowchuk, Mark; Li, Jing; Porter, Karen E.; Ponnambalam, Sreenivasan; Wheatcroft, Stephen B.; Beech, David J.; Kearney, Mark T.

In: Stem Cells, Vol. 32, No. 10, 15.09.2014, p. 2714-2723.

Research output: Contribution to journalArticle

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T1 - Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential

AU - Cubbon, Richard M.

AU - Yuldasheva, Nadira Y.

AU - Viswambharan, Hema

AU - Mercer, Ben N.

AU - Baliga, Vivek

AU - Stephen, Sam L.

AU - Askham, Jonathan

AU - Sukumar, Piruthivi

AU - Skromna, Anna

AU - Mughal, Romana S.

AU - Walker, Andrew M.N.

AU - Bruns, Alexander

AU - Bailey, Marc A.

AU - Galloway, Stacey

AU - Imrie, Helen

AU - Gage, Matthew C.

AU - Rakobowchuk, Mark

AU - Li, Jing

AU - Porter, Karen E.

AU - Ponnambalam, Sreenivasan

AU - Wheatcroft, Stephen B.

AU - Beech, David J.

AU - Kearney, Mark T.

PY - 2014/9/15

Y1 - 2014/9/15

N2 - Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.

AB - Recent data suggest reduced indices of vascular repair in South Asian men, a group at increased risk of cardiovascular events. Outgrowth endothelial cells (OEC) represent an attractive tool to study vascular repair in humans and may offer potential in cell-based repair therapies. We aimed to define and manipulate potential mechanisms of impaired vascular repair in South Asian (SA) men. In vitro and in vivo assays of vascular repair and angiogenesis were performed using OEC derived from SA men and matched European controls, prior defining potentially causal molecular mechanisms. SA OEC exhibited impaired colony formation, migration, and in vitro angiogenesis, associated with decreased expression of the proangiogenic molecules Akt1 and endothelial nitric oxide synthase (eNOS). Transfusion of European OEC into immunodeficient mice after wire-induced femoral artery injury augmented reendothelialization, in contrast with SA OEC and vehicle; SA OEC also failed to promote angiogenesis after induction of hind limb ischemia. Expression of constitutively active Akt1 (E17KAkt), but not green fluorescent protein control, in SA OEC increased in vitro angiogenesis, which was abrogated by a NOS antagonist. Moreover, E17KAkt expressing SA OEC promoted re-endothelialization of wire-injured femoral arteries, and perfusion recovery of ischemic limbs, to a magnitude comparable with nonmanipulated European OEC. Silencing Akt1 in European OEC recapitulated the functional deficits noted in SA OEC. Reduced signaling via the Akt/eNOS axis is causally linked with impaired OEC-mediated vascular repair in South Asian men. These data prove the principle of rescuing marked reparative dysfunction in OEC derived from these men.

KW - Akt

KW - Endothelial

KW - Repair

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Cubbon RM, Yuldasheva NY, Viswambharan H, Mercer BN, Baliga V, Stephen SL et al. Restoring Akt1 activity in outgrowth endothelial cells from south asian men rescues vascular reparative potential. Stem Cells. 2014 Sep 15;32(10):2714-2723. https://doi.org/10.1002/stem.1766