Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy

Nefeli Slavi, Abduqodir H. Toychiev, Stylianos Kosmidis, Jessica Ackert, Stewart A. Bloomfield, Heike Wulff, Suresh Viswanathan, Paul D. Lampe, Miduturu Srinivas

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Degeneration of retinal astrocytes precedes hypoxia-driven pathologic neovascularization and vascular leakage in ischemic retinopathies. However, the molecular events that underlie astrocyte loss remain unclear. Astrocytes abundantly express connexin 43 (Cx43), a transmembrane protein that forms gap junction (GJ) channels and hemichannels. Cx channels can transfer toxic signals from dying cells to healthy neighbors under pathologic conditions. Here we show that Cx43 plays a critical role in astrocyte apoptosis and the resulting preretinal neovascularization in a mouse model of oxygen-induced retinopathy. Opening of Cx43 hemichannels was not observed following hypoxia. In contrast, GJ coupling between astrocytes increased, which could lead to amplification of injury. Accordingly, conditional deletion of Cx43 maintained a higher density of astrocytes in the hypoxic retina. We also identify a role for Cx43 phosphorylation in mediating these processes. Increased coupling in response to hypoxia is due to phosphorylation of Cx43 by casein kinase 1δ (CK1δ). Suppression of this phosphorylation using an inhibitor of CK1δ or in site-specific phosphorylation-deficient mice similarly protected astrocytes from hypoxic damage. Rescue of astrocytes led to restoration of a functional retinal vasculature and lowered the hypoxic burden, thereby curtailing neovascularization and neuroretinal dysfunction. We also find that absence of astrocytic Cx43 does not affect developmental angiogenesis or neuronal function in normoxic retinas. Our in vivo work directly links phosphorylation of Cx43 to astrocytic coupling and apoptosis and ultimately to vascular regeneration in retinal ischemia. This study reveals that targeting Cx43 phosphorylation in astrocytes is a potential direction for the treatment of proliferative retinopathies.

Original languageEnglish (US)
Pages (from-to)E5934-E5943
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number26
DOIs
StatePublished - Jun 26 2018

Fingerprint

Connexin 43
Astrocytes
Blood Vessels
Regeneration
Phosphorylation
Casein Kinase I
Retina
Pathologic Neovascularization
Apoptosis
Retinal Degeneration
Connexins
Poisons
Gap Junctions
Ischemia
Oxygen

Keywords

  • Astrocytes
  • Gap junctions
  • Ischemia
  • Neurovascular
  • Retina

ASJC Scopus subject areas

  • General

Cite this

Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy. / Slavi, Nefeli; Toychiev, Abduqodir H.; Kosmidis, Stylianos; Ackert, Jessica; Bloomfield, Stewart A.; Wulff, Heike; Viswanathan, Suresh; Lampe, Paul D.; Srinivas, Miduturu.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 26, 26.06.2018, p. E5934-E5943.

Research output: Contribution to journalArticle

Slavi, Nefeli ; Toychiev, Abduqodir H. ; Kosmidis, Stylianos ; Ackert, Jessica ; Bloomfield, Stewart A. ; Wulff, Heike ; Viswanathan, Suresh ; Lampe, Paul D. ; Srinivas, Miduturu. / Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 26. pp. E5934-E5943.
@article{6f930cd98498460697fc40c20624db77,
title = "Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy",
abstract = "Degeneration of retinal astrocytes precedes hypoxia-driven pathologic neovascularization and vascular leakage in ischemic retinopathies. However, the molecular events that underlie astrocyte loss remain unclear. Astrocytes abundantly express connexin 43 (Cx43), a transmembrane protein that forms gap junction (GJ) channels and hemichannels. Cx channels can transfer toxic signals from dying cells to healthy neighbors under pathologic conditions. Here we show that Cx43 plays a critical role in astrocyte apoptosis and the resulting preretinal neovascularization in a mouse model of oxygen-induced retinopathy. Opening of Cx43 hemichannels was not observed following hypoxia. In contrast, GJ coupling between astrocytes increased, which could lead to amplification of injury. Accordingly, conditional deletion of Cx43 maintained a higher density of astrocytes in the hypoxic retina. We also identify a role for Cx43 phosphorylation in mediating these processes. Increased coupling in response to hypoxia is due to phosphorylation of Cx43 by casein kinase 1δ (CK1δ). Suppression of this phosphorylation using an inhibitor of CK1δ or in site-specific phosphorylation-deficient mice similarly protected astrocytes from hypoxic damage. Rescue of astrocytes led to restoration of a functional retinal vasculature and lowered the hypoxic burden, thereby curtailing neovascularization and neuroretinal dysfunction. We also find that absence of astrocytic Cx43 does not affect developmental angiogenesis or neuronal function in normoxic retinas. Our in vivo work directly links phosphorylation of Cx43 to astrocytic coupling and apoptosis and ultimately to vascular regeneration in retinal ischemia. This study reveals that targeting Cx43 phosphorylation in astrocytes is a potential direction for the treatment of proliferative retinopathies.",
keywords = "Astrocytes, Gap junctions, Ischemia, Neurovascular, Retina",
author = "Nefeli Slavi and Toychiev, {Abduqodir H.} and Stylianos Kosmidis and Jessica Ackert and Bloomfield, {Stewart A.} and Heike Wulff and Suresh Viswanathan and Lampe, {Paul D.} and Miduturu Srinivas",
year = "2018",
month = "6",
day = "26",
doi = "10.1073/pnas.1803907115",
language = "English (US)",
volume = "115",
pages = "E5934--E5943",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "26",

}

TY - JOUR

T1 - Suppression of connexin 43 phosphorylation promotes astrocyte survival and vascular regeneration in proliferative retinopathy

AU - Slavi, Nefeli

AU - Toychiev, Abduqodir H.

AU - Kosmidis, Stylianos

AU - Ackert, Jessica

AU - Bloomfield, Stewart A.

AU - Wulff, Heike

AU - Viswanathan, Suresh

AU - Lampe, Paul D.

AU - Srinivas, Miduturu

PY - 2018/6/26

Y1 - 2018/6/26

N2 - Degeneration of retinal astrocytes precedes hypoxia-driven pathologic neovascularization and vascular leakage in ischemic retinopathies. However, the molecular events that underlie astrocyte loss remain unclear. Astrocytes abundantly express connexin 43 (Cx43), a transmembrane protein that forms gap junction (GJ) channels and hemichannels. Cx channels can transfer toxic signals from dying cells to healthy neighbors under pathologic conditions. Here we show that Cx43 plays a critical role in astrocyte apoptosis and the resulting preretinal neovascularization in a mouse model of oxygen-induced retinopathy. Opening of Cx43 hemichannels was not observed following hypoxia. In contrast, GJ coupling between astrocytes increased, which could lead to amplification of injury. Accordingly, conditional deletion of Cx43 maintained a higher density of astrocytes in the hypoxic retina. We also identify a role for Cx43 phosphorylation in mediating these processes. Increased coupling in response to hypoxia is due to phosphorylation of Cx43 by casein kinase 1δ (CK1δ). Suppression of this phosphorylation using an inhibitor of CK1δ or in site-specific phosphorylation-deficient mice similarly protected astrocytes from hypoxic damage. Rescue of astrocytes led to restoration of a functional retinal vasculature and lowered the hypoxic burden, thereby curtailing neovascularization and neuroretinal dysfunction. We also find that absence of astrocytic Cx43 does not affect developmental angiogenesis or neuronal function in normoxic retinas. Our in vivo work directly links phosphorylation of Cx43 to astrocytic coupling and apoptosis and ultimately to vascular regeneration in retinal ischemia. This study reveals that targeting Cx43 phosphorylation in astrocytes is a potential direction for the treatment of proliferative retinopathies.

AB - Degeneration of retinal astrocytes precedes hypoxia-driven pathologic neovascularization and vascular leakage in ischemic retinopathies. However, the molecular events that underlie astrocyte loss remain unclear. Astrocytes abundantly express connexin 43 (Cx43), a transmembrane protein that forms gap junction (GJ) channels and hemichannels. Cx channels can transfer toxic signals from dying cells to healthy neighbors under pathologic conditions. Here we show that Cx43 plays a critical role in astrocyte apoptosis and the resulting preretinal neovascularization in a mouse model of oxygen-induced retinopathy. Opening of Cx43 hemichannels was not observed following hypoxia. In contrast, GJ coupling between astrocytes increased, which could lead to amplification of injury. Accordingly, conditional deletion of Cx43 maintained a higher density of astrocytes in the hypoxic retina. We also identify a role for Cx43 phosphorylation in mediating these processes. Increased coupling in response to hypoxia is due to phosphorylation of Cx43 by casein kinase 1δ (CK1δ). Suppression of this phosphorylation using an inhibitor of CK1δ or in site-specific phosphorylation-deficient mice similarly protected astrocytes from hypoxic damage. Rescue of astrocytes led to restoration of a functional retinal vasculature and lowered the hypoxic burden, thereby curtailing neovascularization and neuroretinal dysfunction. We also find that absence of astrocytic Cx43 does not affect developmental angiogenesis or neuronal function in normoxic retinas. Our in vivo work directly links phosphorylation of Cx43 to astrocytic coupling and apoptosis and ultimately to vascular regeneration in retinal ischemia. This study reveals that targeting Cx43 phosphorylation in astrocytes is a potential direction for the treatment of proliferative retinopathies.

KW - Astrocytes

KW - Gap junctions

KW - Ischemia

KW - Neurovascular

KW - Retina

UR - http://www.scopus.com/inward/record.url?scp=85049015156&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85049015156&partnerID=8YFLogxK

U2 - 10.1073/pnas.1803907115

DO - 10.1073/pnas.1803907115

M3 - Article

VL - 115

SP - E5934-E5943

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 26

ER -