Endothelial connexin32 enhances angiogenesis by positively regulating tube formation and cell migration

Okamoto, Takayuki; Akita, Nobuyuki; Kawamoto, Eiji; Hayashi, Tatsuya; Suzuki, Koji; Shimaoka, Motomu

doi:10.1016/j.yexcr.2013.12.002

Cited by 30 publications

(38 citation statements)

References 43 publications

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“…HUVECs endogenously express Cx32, Cx37, Cx40, and Cx43, which form GJs 27 . We previously showed that Cx32 and Cx43 in HUVECs contribute more to the functional phenotypes of ECs than do Cx37 and Cx40 35, 36 . We therefore focused on Cx32 and Cx43, and intracellularly delivered anti-Cx32 mAb or anti-Cx43 mAb into HUVECs in order to block Cx32- and/or Cx43-mediated GJs (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Subsequently, we blocked GJ functionality via an alternative approach involving intracellular delivery of antibodies to the cytoplasmic domain of Cx 35, 36 . While the GJ inhibitors CBX and oleamide non-selectively inhibited Cxs 42, 43 , intracellularly transferred anti-Cxs monoclonal antibody (mAb) blocked Cx-specific GJ formation and function.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously shown that the Cx32-mediated intercellular transfer of small molecules decreases upon inflammation 34 , and that aberrant endothelial Cx32 increases pro-inflammatory cytokines 34 and pro-coagulant tissue factor expression 35 . Furthermore, we have shown that Cx32 enhances angiogenesis-related endothelial tube formation and migration, while Cx43 reduces them 36 . Although EC-EC communications via Cxs have been shown to regulate many EC functions such as leukocyte adhesion 29, 30 , vascular permeability 37 , and angiogenesis 38 , it remains to be determined how Cxs regulate cellular stiffness.…”

Section: Introductionmentioning

confidence: 85%

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Gap junction-mediated regulation of endothelial cellular stiffness

Okamoto

Kawamoto

Takagi

et al. 2017

Sci Rep

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Endothelial monolayers have shown the ability to signal each other through gap junctions. Gap junction-mediated cell-cell interactions have been implicated in the modulation of endothelial cell functions during vascular inflammation. Inflammatory mediators alter the mechanical properties of endothelial cells, although the exact role of gap junctions in this process remains unclear. Here, we sought to study the role of gap junctions in the regulation of endothelial stiffness, an important physical feature that is associated with many vascular pathologies. The endothelial cellular stiffness of living endothelial cells was determined by using atomic force microscopy. We found that tumor necrosis factor-α transiently increased endothelial cellular stiffness, which is regulated by cytoskeletal rearrangement and cell-cell interactions. We explored the role of gap junctions in endothelial cellular stiffening by utilizing gap junction blockers, carbenoxolone, inhibitory anti-connexin 32 antibody or anti-connexin 43 antibody. Blockade of gap junctions induced the cellular stiffening associated with focal adhesion formation and cytoskeletal rearrangement, and prolonged tumor necrosis factor-α-induced endothelial cellular stiffening. These results suggest that gap junction-mediated cell-cell interactions play an important role in the regulation of endothelial cellular stiffness.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

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Gap junction-mediated regulation of endothelial cellular stiffness

Okamoto

Kawamoto

Takagi

et al. 2017

Sci Rep

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“…In addition to VE-cadherin, an adherens junctional protein critical to maintaining EC permeability [50], the hCB-EPC microvessels also expressed the gap-junctional protein connexin 32, (Figure 5B) an important component to EC intercellular communication and tube formation [51–52]. As well, the hCB-EPC microvessels expressed eNOS (Figure 5C), which helps prevent thrombosis by discouraging platelet adhesion [53].…”

Section: Resultsmentioning

confidence: 99%

Poly(Ethylene Glycol) Hydrogel Scaffolds Containing Cell-Adhesive and Protease-Sensitive Peptides Support Microvessel Formation by Endothelial Progenitor Cells

et al. 2015

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The development of stable, functional microvessels remains an important obstacle to overcome for tissue engineered organs and treatment of ischemia. Endothelial progenitor cells (EPCs) are a promising cell source for vascular tissue engineering as they are readily obtainable and carry the potential to differentiate towards all endothelial phenotypes. The aim of this study was to investigate the ability of human umbilical cord blood-derived EPCs to form vessel-like structures within a tissue engineering scaffold material, a cell-adhesive and proteolytically degradable poly(ethylene glycol) (PEG) hydrogel. EPCs in co-culture with angiogenic mural cells were encapsulated in hydrogel scaffolds by mixing with polymeric precursors and using a mild photocrosslinking process to form hydrogels with homogeneously dispersed cells. EPCs formed 3D microvessels networks that were stable for at least 30 days in culture, without the need for supplemental angiogenic growth factors. These 3D EPC microvessels displayed aspects of physiological microvasculature with lumen formation, expression of endothelial cell proteins (connexin 32, VE-cadherin, eNOS), basement membrane formation with collagen IV and laminin, perivascular investment of PDGFR-β and α-SMA positive cells, and EPC quiescence (<1% proliferating cells) by 2 weeks of co-culture. Our findings demonstrate the development of a novel, reductionist system that is well-defined and reproducible for studying progenitor cell-driven microvessel formation.

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“…It is important to be aware of potential pitfalls, including effects of channel blockers on other putative connexin roles in tumours. Connexins have for example been proposed to be acting as tumour suppressors [see for example 80] and Cx32 is said to enhance endothelial cell migration and tube formation [81]. Furthermore, vessel co‐option whereby tumour cells migrate along pre‐existing vessels [82] may be compounded with improved vascular integrity.…”

Section: The Paradigm Shiftmentioning

confidence: 99%

Connexin hemichannel induced vascular leak suggests a new paradigm for cancer therapy

et al. 2014

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a b s t r a c tIt is 40 years since cancer growth was correlated with neovascularisation. Anti-angiogenic drugs remain at the forefront of cancer investigations but progress has been disappointing and unexpected toxicities are emerging. Gap junction channels are implicated in lesion spread following injury, with channel blockers shown to improve healing; in particular preventing vascular disruption and/or restoring vascular integrity. Here we briefly review connexin roles in vascular leak and endothelial cell death that occurs following acute wounds and during chronic disease, and how connexin channel regulation has been used to ameliorate vascular disruption. We then review chronic inflammatory disorders and trauma in the eye, concluding that vascular disruption under these conditions mimics that seen in tumours, and can be prevented with connexin hemichannel modulation. We apply this knowledge to tumour vessel biology, proposing that contrary to current opinion, these data suggest a need to protect, maintain and/or restore cancer vasculature. This may lead to reduced tumour hypoxia, promote the survival of normal cells, and enable improved therapeutic delivery or more effective radiation therapy.

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Endothelial connexin32 enhances angiogenesis by positively regulating tube formation and cell migration

Cited by 30 publications

References 43 publications

Gap junction-mediated regulation of endothelial cellular stiffness

Gap junction-mediated regulation of endothelial cellular stiffness

Poly(Ethylene Glycol) Hydrogel Scaffolds Containing Cell-Adhesive and Protease-Sensitive Peptides Support Microvessel Formation by Endothelial Progenitor Cells

Connexin hemichannel induced vascular leak suggests a new paradigm for cancer therapy

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