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Targeting Cx40 (Connexin40) Expression or Function Reduces Angiogenesis in the Developing Mouse Retina
Jacques-Antoine Haefliger1, Florent Allagnat2, Lauriane Hamard2
1From the Department of Medicine (J.-A.H., F.A., L.H., L.L.G., F.A.) and Department of Urology (D.N.H.), Lausanne University Hospital, Switzerland; Department of Cell Physiology and Metabolism, University of Geneva Medical Center, Switzerland (P.M.); and Centre de Recherche Cardio-Thoracique de Bordeaux (INSERM U1045), Université de Bordeaux, France (E.G., F.A.). florian.alonso@u-bordeaux.fr Jacques-Antoine.Haefliger@chuv.ch.
Insights
Connexin40 (Cx40) protein is crucial for physiological angiogenesis, regulating vascular growth and maturation in the retina. Loss of Cx40 impairs blood vessel development, highlighting its therapeutic potential for ocular angiogenesis.
Area of Science:
- Vascular biology
- Cellular signaling
- Ophthalmology
Background:
- Connexin40 (Cx40) facilitates intercellular communication, influencing cardiac electrical conduction and vascular tone.
- Cx40's role in tumoral angiogenesis is established, but its contribution to physiological angiogenesis remains unclear.
Purpose of the Study:
- To investigate the role of Cx40 in physiological angiogenesis.
- To determine if Cx40 regulates vascular growth and development in the retina.
Main Methods:
- Utilized a mouse neonatal retinal neovascularization model.
- Genetic deletion and reexpression of Cx40 in endothelial cells.
- In vitro studies involving microvascular endothelial cell proliferation and PDGF release.
- In vivo administration of a Cx40 inhibitory peptide.
Main Results:
- Genetic deletion of Cx40 reduced vascular growth and capillary density in the retina.
- Cx40 deficiency impaired vessel sprouting and altered mural cell phenotype.
- Cx40 reexpression restored normal angiogenesis, indicating endothelial cell-specific function.
- In vitro, Cx40 loss decreased endothelial cell proliferation and increased mural cell chemoattraction.
- Cx40 inhibition mimicked genetic deletion effects in vivo.
Conclusions:
- Endothelial Cx40 is essential for physiological angiogenesis in the developing retina.
- Cx40 regulates early-stage angiogenesis, impacting vessel growth and maturation.
- Cx40 emerges as a potential therapeutic target for pathological ocular angiogenesis.
Objective:
Cx40 (Connexin40) forms intercellular channels that coordinate the electric conduction in the heart and the vasomotor tone in large vessels. The protein was shown to regulate tumoral angiogenesis; however, whether Cx40 also contributes to physiological angiogenesis is still unknown.
Approach And Results:
Here, we show that Cx40 contributes to physiological angiogenesis. Genetic deletion of Cx40 leads to a reduction in vascular growth and capillary density in the neovascularization model of the mouse neonatal retina. At the angiogenic front, vessel sprouting is reduced, and the mural cells recruited along the sprouts display an altered phenotype. These alterations can be attributed to disturbed endothelial cell functions as selective reexpression of Cx40 in these cells restores normal angiogenesis. In vitro, targeting Cx40 in microvascular endothelial cells, by silencing its expression or by blocking gap junction channels, decreases their proliferation. Moreover, loss of Cx40 in these cells also increases their release of PDGF (platelet-derived growth factor) and promotes the chemoattraction of mural cells. In vivo, an intravitreal injection of a Cx40 inhibitory peptide, phenocopies the loss of Cx40 in the retinal vasculature of wild-type mice.
Conclusions:
Collectively, our data show that endothelial Cx40 contributes to the early stages of physiological angiogenesis in the developing retina, by regulating vessel growth and maturation. Cx40 thus represents a novel therapeutic target for treating pathological ocular angiogenesis.
