Gap Junction Communication Mediates Transforming Growth Factor-β Activation and Endothelial-Induced Mural Cell Differentiation
Open accessAbstract
During blood vessel assembly, endothelial cells recruit mesenchymal progenitors and induce their differentiation into mural cells via contact-dependent transforming growth factor-β (TGF-β) activation. We investigated whether gap junction channels are formed between endothelial cells and recruited mesenchymal progenitors and whether intercellular communication is necessary for endothelial-induced mural cell differentiation. Mesenchymal progenitors from Cx43 −/− murine embryos and Cx43 +/+ littermates were cocultured with prelabeled endothelial cells. Intracellular dye injection and dual whole-cell voltage clamp revealed that endothelial cells formed gap junction channels with Cx43 +/+ but not Cx43 −/− progenitors. In coculture with endothelial cells, Cx43 −/− progenitors did not undergo mural cell differentiation as did Cx43 +/+ cells. Stable reexpression of Cx43 in Cx43 −/− cells (reCx43) restored their ability to form gap junctions with endothelial cells and undergo endothelial-induced mural cell differentiation. Cocultures of endothelial cells and either Cx43 +/+ or reCx43 mesenchymal cells produced activated TGF-β; endothelial-Cx43 −/− cocultures did not. However, Cx43 −/− cells did produce latent TGF-β and undergo mural cell differentiation in response to exogenous TGF-β1. These studies indicate that gap junction communication between endothelial and mesenchymal cells mediates TGF-β activation and subsequent mural cell differentiation.
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Gap junction CX43 hemichannels enable intercellular communications between pericytes and endothelial cells.
“Gap junction CX43 hemichannels (112, 251, 347) enable intercellular communications between pericytes and endothelial cells (570, 648, 682).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [251]
The figure 1 legend reports dye transfer and functional Cx43-containing gap junction channels between endothelial cells and Cx43-positive mesenchymal cells. The Cell Culture section identifies those cells as mural-cell progenitors, not pericytes; the paper also does not specifically test Cx43 hemichannels. Thus it supports the intercellular-communication mechanism but not the claim at that cellular and channel specificity. (LLM, conf=0.87)
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References 47 · Cited by 176
Research works printed but not linked: 4
- Hirschi KK, Rohovsky SA, Smith SR, Beck LH, D'Amore PA. Endo- thelial cells modulate the proliferation of mural cell precursors via PDGF-BB and heterotypic cell contact. Circ Res. 1999;84:298 -305.
- Sweet E, Abraham EH, D'Amore PA. Functional evidence of gap junctions between capillary endothelial cells and pericytes in vitro. Invest Ophthalmol Vis Sci. 1988;29:109a. Abstract.
- Theis M, deWit C, Schlaeger TM, Eckhardt D, Kruger O, Doring B, Rissau W, Deutsch U, Pohl U, Willecke K. Endothelium-specific replacement of the connexin43 coding region by a lacZ reporter gene. Genesis. 2001;29:1-13.
- Kruger O, Plum A, Kim J-S, Winterhager E, Maxeiner S, Hallas G, Kirchhoff S, Traub O, Lamers WH, Willecke K. Defective vascular development in connexin45-deficient mice. Development. 2000;127: 4179 -4193.
- Authors
- Hirschi, K. K., Burt, J. M., Hirschi, K. D., & Dai, C.
- Affiliations
- University of Arizona (US)
- Venue
- Circulation Research
- Published
- 2003-09-05
- Volume
- 93
- Issue
- 5
- Pages
- 429-437
- ISSN
- 0009-7330 (ISSN-L)
- 1524-4571
- OpenAlex
- W1985186457
- Cited by
- 176
- References
- 47
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 10 · 2021: 7 · 2020: 8 · 2019: 7 · 2018: 5 · 2017: 12 · 2016: 8 · 2015: 9 · 2014: 14 · 2013: 8 · 2012: 10
- FWCI
- 2.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Circulation Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Agriculture (6250‐51000)
- American Heart Association
- National Institutes of Health (5r01hl058732-16, 5r01gm057427-05)
- National Heart, Lung, and Blood Institute (R01HL061408, R01-HL58732-1)
- National Institute of General Medical Sciences (R01 GM 57427)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Connexins and lens biology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Keywords
- gap junctional intercellular communication, connexin 43, mesenchymal progenitor cells, intercellular communication, latent TGF-beta, endothelial cells
- MeSH terms
- Animals, Cattle, Cell Communication, Cell Differentiation, Cells, Cultured, Endothelium, Vascular, Fluorescent Dyes, Immunohistochemistry, Isoquinolines, Membrane Potentials, Mesoderm, Microinjections, Gene Expression, Transforming Growth Factor beta, Gap Junctions, Connexin 43, Mice, Knockout, Patch-Clamp Techniques, Coculture Techniques, Mice
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