Structural Determinants and Proliferative Consequences of Connexin 37 Hemichannel Function in Insulinoma Cells

Good, Miranda E.; Ek‐Vitorín, José F.; Burt, Janis M.

doi:10.1074/jbc.m114.583054

Cited by 16 publications

(20 citation statements)

References 34 publications

(46 reference statements)

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“…This distribution outside of the cellular contacts suggests that Cx37 may form hemichannels on the surface of the vascular cells. As we did not observe Neurobiotin spread from the surface of the vascular cells expressing Cx37, these hemichannels may normally remain closed, as was demonstrated for various hemichannels (for review, see Good, Ek‐Vitorin, & Burt, ; Goodenough & Paul, ).…”

Section: Resultssupporting

confidence: 67%

Domain‐specific distribution of gap junctions defines cellular coupling to establish a vascular relay in the retina

Ivanova

Kovács-Öller

Sagdullaev

2019

J of Comparative Neurology

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In the retina, diverse functions of neuronal gap junctions (GJs) have been established. However, the distribution and function of vascular GJs are less clear. Here in the mouse retina whole mounts, we combined structural immunohistochemical analysis and a functional assessment of cellular coupling with a GJ‐permeable tracer Neurobiotin to determine distribution patterns of three major vascular connexins. We found that Cx43 was expressed in punctate fashion on astroglia, surrounding all types of blood vessels and in continuous string‐like structures along endothelial cell contacts in specialized regions of the vascular tree. Specifically, these Cx43‐positive strings originated at the finest capillaries and extended toward the feeding artery. As this structural arrangement promoted strong and exclusive coupling of pericytes and endothelial cells along the corresponding branch, we termed this region a “vascular relay.” Cx40 expression was found predominantly along the endothelial cell contacts of the primary arteries and did not overlap with Cx43‐positive strings. At their occupied territories, Cx43 and Cx40 clustered with tight junctions and, to a lesser extent, with adhesion contacts, both key elements of the blood–retina barrier. Finally, Cx37 puncta were associated with the entire surface of both mural and endothelial cells across all regions of the vascular tree. This combinatorial analysis of vascular connexins and identification of the vascular relay region will serve as a structural foundation for future studies of neurovascular signaling in health and disease.

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Section: Resultssupporting

confidence: 67%

Domain‐specific distribution of gap junctions defines cellular coupling to establish a vascular relay in the retina

Ivanova

Kovács-Öller

Sagdullaev

2019

J of Comparative Neurology

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“…This finding is consistent with studies reporting that Cx37 is growth suppressive (Burt et al, 2008; Fang et al, 2011). The exact mechanism by which Cx37 controls growth is unknown; however, its ability to form a channel capable of supporting intercellular, transmembrane, and intracellular signaling is necessary for growth suppression in cell culture settings (Good et al, 2014). …”

Section: Discussionmentioning

confidence: 99%

Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling

Kanady

Munger

Witte

et al. 2015

Developmental Biology

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Connexins (Cxs), proteins that are vital for intercellular communication in vertebrates, have recently been shown to play a critical role in lymphatic development. However, our knowledge is currently limited regarding the functional relationships of Cxs with other proteins and signaling pathways. Cell culture studies have shown that Cx37 is necessary for coordinated activation of the transcription factor NFATc1, which cooperates with Foxc2 (another transcription factor) during lymphatic endothelial development. These data suggest that Cxs, Foxc2, and NFATc1 are part of a common developmental pathway. Here, we present a detailed characterization of Foxc2 +/−Cx37 −/− mice, demonstrating that lymphatic network architecture and valve formation rely on the concurrent embryonic expression and function of Foxc2 and Cx37. Foxc2 +/−Cx37−/− mice have lymphedema in utero, exhibit craniofacial abnormalities, show severe dilation of intestinal lymphatics, display abnormal lacteal development, lack lymphatic valves, and typically die perinatally (outcomes not seen in Foxc2 +/− or Cx37−/− mice separately). We provide a rigorous, quantitative documentation of lymphatic vascular network changes that highlight the specific structural alterations that occur in Foxc2+/− Cx37−/− mice. These data provide further evidence suggesting that Foxc2 and Cx37 are elements in a common molecular pathway directing lymphangiogenesis.

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“…21 The same group also demonstrated in rat insulinoma cells that the antiproliferative effect of Cx37 requires an intact gap junction channel function and that formation of hemichannels cannot explain the effect. 245 A reduction of Cx43 in Cx43+/À animals led to pericyte loss and an increased amount of acellular capillaries in the retinal microcirculation, changes which are also observed in diabetic animals. 246 It should be noted that in experimental hypertension changes in connexin expression in blood vessels have been reported.…”

Section: Animalsmentioning

confidence: 93%

Connexins in the control of vasomotor function

Pogoda

Kameritsch

Mannell³

et al. 2018

Acta Physiologica

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Vascular endothelial cells, as well as smooth muscle cells, show heterogeneity with regard to their receptor expression and reactivity. For the vascular wall to act as a functional unit, the various cells' responses require integration. Such an integration is not only required for a homogeneous response of the vascular wall, but also for the vasomotor behaviour of consecutive segments of the microvascular arteriolar tree. As flow resistances of individual sections are connected in series, sections require synchronization and coordination to allow effective changes of conductivity and blood flow. A prerequisite for the local coordination of individual vascular cells and different sections of an arteriolar tree is intercellular communication. Connexins are involved in a dual manner in this coordination. (i) By forming gap junctions between cells, they allow an intercellular exchange of signalling molecules and electrical currents. In particular, the spread of electrical currents allows for coordination of cell responses over longer distances. (ii) Connexins are able to interact with other proteins to form signalling complexes. In this way, they can modulate and integrate individual cells' responses also in a channel-independent manner. This review outlines mechanisms allowing the vascular connexins to exert their coordinating function and to regulate the vasomotor reactions of blood vessels both locally, and in vascular networks. Wherever possible, we focus on the vasomotor behaviour of small vessels and arterioles which are the main vessels determining vascular resistance, blood pressure and local blood flow.

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Structural Determinants and Proliferative Consequences of Connexin 37 Hemichannel Function in Insulinoma Cells

Cited by 16 publications

References 34 publications

Domain‐specific distribution of gap junctions defines cellular coupling to establish a vascular relay in the retina

Domain‐specific distribution of gap junctions defines cellular coupling to establish a vascular relay in the retina

Combining Foxc2 and Connexin37 deletions in mice leads to severe defects in lymphatic vascular growth and remodeling

Connexins in the control of vasomotor function

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