Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice

Anshuman Sengupta, Peysh A. Patel, Nadira Y. Yuldasheva, Romana S. Mughal, Stacey Galloway, Hema Viswambharan, Andrew M.N. Walker, Amir Aziz, Jessica Smith, Noman Ali, Ben N. Mercer, Helen Imrie, Piruthivi Sukumar, Stephen B. Wheatcroft, Mark T. Kearney, Richard M. Cubbon

Research output: Contribution to journalArticle

Abstract

Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell-specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- A nd insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

LanguageEnglish
Pages2917-2925
Number of pages9
JournalEndocrinology
Volume159
Issue number8
Early online date15 May 2018
DOIs
Publication statusPublished - 1 Aug 2018
Externally publishedYes

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Insulin Receptor
Blood Vessels
Endothelial Cells
Insulin
Myeloid Cells
Glucose Tolerance Test
Knockout Mice
Vasodilation
Acetylcholine
Cell Movement
Arterial Pressure
Nitric Oxide
human INSR protein
Phenotype
Wounds and Injuries

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Sengupta, A., Patel, P. A., Yuldasheva, N. Y., Mughal, R. S., Galloway, S., Viswambharan, H., ... Cubbon, R. M. (2018). Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice. Endocrinology, 159(8), 2917-2925. https://doi.org/10.1210/en.2018-00215
Sengupta, Anshuman ; Patel, Peysh A. ; Yuldasheva, Nadira Y. ; Mughal, Romana S. ; Galloway, Stacey ; Viswambharan, Hema ; Walker, Andrew M.N. ; Aziz, Amir ; Smith, Jessica ; Ali, Noman ; Mercer, Ben N. ; Imrie, Helen ; Sukumar, Piruthivi ; Wheatcroft, Stephen B. ; Kearney, Mark T. ; Cubbon, Richard M. / Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice. In: Endocrinology. 2018 ; Vol. 159, No. 8. pp. 2917-2925.
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Sengupta, A, Patel, PA, Yuldasheva, NY, Mughal, RS, Galloway, S, Viswambharan, H, Walker, AMN, Aziz, A, Smith, J, Ali, N, Mercer, BN, Imrie, H, Sukumar, P, Wheatcroft, SB, Kearney, MT & Cubbon, RM 2018, 'Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice', Endocrinology, vol. 159, no. 8, pp. 2917-2925. https://doi.org/10.1210/en.2018-00215

Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice. / Sengupta, Anshuman; Patel, Peysh A.; Yuldasheva, Nadira Y.; Mughal, Romana S.; Galloway, Stacey; Viswambharan, Hema; Walker, Andrew M.N.; Aziz, Amir; Smith, Jessica; Ali, Noman; Mercer, Ben N.; Imrie, Helen; Sukumar, Piruthivi; Wheatcroft, Stephen B.; Kearney, Mark T.; Cubbon, Richard M.

In: Endocrinology, Vol. 159, No. 8, 01.08.2018, p. 2917-2925.

Research output: Contribution to journalArticle

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T1 - Endothelial insulin receptor restoration rescues vascular function in male insulin receptor haploinsufficient mice

AU - Sengupta, Anshuman

AU - Patel, Peysh A.

AU - Yuldasheva, Nadira Y.

AU - Mughal, Romana S.

AU - Galloway, Stacey

AU - Viswambharan, Hema

AU - Walker, Andrew M.N.

AU - Aziz, Amir

AU - Smith, Jessica

AU - Ali, Noman

AU - Mercer, Ben N.

AU - Imrie, Helen

AU - Sukumar, Piruthivi

AU - Wheatcroft, Stephen B.

AU - Kearney, Mark T.

AU - Cubbon, Richard M.

PY - 2018/8/1

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N2 - Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell-specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- A nd insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

AB - Reduced systemic insulin signaling promotes endothelial dysfunction and diminished endogenous vascular repair. We investigated whether restoration of endothelial insulin receptor expression could rescue this phenotype. Insulin receptor knockout (IRKO) mice were crossed with mice expressing a human insulin receptor endothelial cell-specific overexpression (hIRECO) to produce IRKO-hIRECO progeny. No metabolic differences were noted between IRKO and IRKO-hIRECO mice in glucose and insulin tolerance tests. In contrast with control IRKO littermates, IRKO-hIRECO mice exhibited normal blood pressure and aortic vasodilatation in response to acetylcholine, comparable to parameters noted in wild type littermates. These phenotypic changes were associated with increased basal- A nd insulin-stimulated nitric oxide production. IRKO-hIRECO mice also demonstrated normalized endothelial repair after denuding arterial injury, which was associated with rescued endothelial cell migration in vitro but not with changes in circulating progenitor populations or culture-derived myeloid angiogenic cells. These data show that restoration of endothelial insulin receptor expression alone is sufficient to prevent the vascular dysfunction caused by systemically reduced insulin signaling.

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EP - 2925

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