Mechanisms of vascular dysfunction in the interleukin-10–deficient murine model of preeclampsia indicate nitric oxide dysregulation

Hajrunisa Cubro; Karl A. Nath; Sonja Suvakov; Oscar Garcia-Valencia; Santosh Parashuram; Wendy M. White; Tracey L. Weissgerber; Meryl C. Nath; Natasa M. Milic; Fernando Sontag; Livius V. d'Uscio; Yi Zhu; James L. Kirkland; Tamar Tchkonia; Mariam P. Alexander; Reade A. Quinton; Zvonimir S. Katusic; Joseph P. Grande; Vesna D. Garovic

doi:10.1016/j.kint.2020.09.034

Mechanisms of vascular dysfunction in the interleukin-10–deficient murine model of preeclampsia indicate nitric oxide dysregulation

Hajrunisa Cubro, Karl A. Nath, Sonja Suvakov, Oscar Garcia-Valencia, Santosh Parashuram, Wendy M. White, Tracey L. Weissgerber, Meryl C. Nath, Natasa M. Milic, Fernando Sontag, Livius V. d'Uscio, Yi Zhu, James L. Kirkland, Tamar Tchkonia, Mariam P. Alexander, Reade A. Quinton, Zvonimir S. Katusic, Joseph P. Grande, Vesna D. Garovic

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1 Scopus citations

Abstract

Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin-10-/- mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10-/- mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10-/- mice injected with sPE sera (IL-10-/-sPE). Vasomotor function of isolated aortas was assessed. The IL-10-/-sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10-/-sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10-/-sPE murine model of preeclampsia and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

Original language	English (US)
Pages (from-to)	646-656
Number of pages	11
Journal	Kidney international
Volume	99
Issue number	3
DOIs	https://doi.org/10.1016/j.kint.2020.09.034
State	Published - Mar 2021

Keywords

interleukin-10
mouse
preeclampsia
vascular reactivity

ASJC Scopus subject areas

Nephrology

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10.1016/j.kint.2020.09.034

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Cubro, H., Nath, K. A., Suvakov, S., Garcia-Valencia, O., Parashuram, S., White, W. M., Weissgerber, T. L., Nath, M. C., Milic, N. M., Sontag, F., d'Uscio, L. V., Zhu, Y., Kirkland, J. L., Tchkonia, T., Alexander, M. P., Quinton, R. A., Katusic, Z. S., Grande, J. P., & Garovic, V. D. (2021). Mechanisms of vascular dysfunction in the interleukin-10–deficient murine model of preeclampsia indicate nitric oxide dysregulation. Kidney international, 99(3), 646-656. https://doi.org/10.1016/j.kint.2020.09.034

Cubro, H, Nath, KA, Suvakov, S, Garcia-Valencia, O, Parashuram, S, White, WM, Weissgerber, TL, Nath, MC, Milic, NM, Sontag, F, d'Uscio, LV, Zhu, Y , Kirkland, JL , Tchkonia, T , Alexander, MP, Quinton, RA, Katusic, ZS, Grande, JP & Garovic, VD 2021, 'Mechanisms of vascular dysfunction in the interleukin-10–deficient murine model of preeclampsia indicate nitric oxide dysregulation', Kidney international, vol. 99, no. 3, pp. 646-656. https://doi.org/10.1016/j.kint.2020.09.034

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title = "Mechanisms of vascular dysfunction in the interleukin-10–deficient murine model of preeclampsia indicate nitric oxide dysregulation",

abstract = "Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin-10-/- mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10-/- mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10-/- mice injected with sPE sera (IL-10-/-sPE). Vasomotor function of isolated aortas was assessed. The IL-10-/-sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10-/-sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10-/-sPE murine model of preeclampsia and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.",

keywords = "interleukin-10, mouse, preeclampsia, vascular reactivity",

author = "Hajrunisa Cubro and Nath, {Karl A.} and Sonja Suvakov and Oscar Garcia-Valencia and Santosh Parashuram and White, {Wendy M.} and Weissgerber, {Tracey L.} and Nath, {Meryl C.} and Milic, {Natasa M.} and Fernando Sontag and d'Uscio, {Livius V.} and Yi Zhu and Kirkland, {James L.} and Tamar Tchkonia and Alexander, {Mariam P.} and Quinton, {Reade A.} and Katusic, {Zvonimir S.} and Grande, {Joseph P.} and Garovic, {Vesna D.}",

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year = "2021",

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doi = "10.1016/j.kint.2020.09.034",

language = "English (US)",

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AU - Cubro, Hajrunisa

AU - Nath, Karl A.

AU - Suvakov, Sonja

AU - Garcia-Valencia, Oscar

AU - Parashuram, Santosh

AU - White, Wendy M.

AU - Weissgerber, Tracey L.

AU - Nath, Meryl C.

AU - Milic, Natasa M.

AU - Sontag, Fernando

AU - d'Uscio, Livius V.

AU - Zhu, Yi

AU - Kirkland, James L.

AU - Tchkonia, Tamar

AU - Alexander, Mariam P.

AU - Quinton, Reade A.

AU - Katusic, Zvonimir S.

AU - Grande, Joseph P.

AU - Garovic, Vesna D.

PY - 2021/3

Y1 - 2021/3

N2 - Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin-10-/- mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10-/- mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10-/- mice injected with sPE sera (IL-10-/-sPE). Vasomotor function of isolated aortas was assessed. The IL-10-/-sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10-/-sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10-/-sPE murine model of preeclampsia and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

AB - Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin-10-/- mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10-/- mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10-/- mice injected with sPE sera (IL-10-/-sPE). Vasomotor function of isolated aortas was assessed. The IL-10-/-sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10-/-sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10-/-sPE murine model of preeclampsia and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia.

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Mechanisms of vascular dysfunction in the interleukin-10–deficient murine model of preeclampsia indicate nitric oxide dysregulation

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