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Analysis of Combinatorial miRNA Treatments to Regulate Cell Cycle and Angiogenesis
Published on: March 30, 2019
miR-155 regulates physiological angiogenesis but an miR-155-rich microenvironment disrupts the process by promoting
Yuechao Dong1, Florian Alonso1, Tiya Jahjah1
1Univ. Bordeaux, INSERM, Centre de Recherche cardio-thoracique de Bordeaux, U1045, 33000, Bordeaux, France.
Abstract:
Angiogenesis involves cell specification orchestrated by regulatory interactions between the vascular endothelial growth factor and Notch signaling pathways. However, the role of microRNAs in these regulations remains poorly explored. Here we show that a controlled level of miR-155 is essential for proper angiogenesis. In the mouse retina angiogenesis model, antimiR-155 altered neovascularization. In vitro assays established that endogenous miR-155 is involved in podosome formation, activation of the proteolytic machinery and cell migration but not in morphogenesis. The role of miR-155 was explored using miR-155 mimics. In vivo, exposing the developing vasculature to miR-155 promoted hypersprouting, thus phenocopying defects associated with Notch deficiency. Mechanistically, miR-155 overexpression weakened Notch signaling by reducing Smad1/5 expression, leading to the formation of tip cell-like cells which did not reach full invasive capacity and became unable to undergo morphogenesis. These results identify miR-155 as a novel regulator of physiological angiogenesis and as a novel actor of pathological angiogenesis.
Insights
A controlled level of microRNA-155 (miR-155) is crucial for blood vessel formation (angiogenesis). Dysregulation of miR-155 impacts neovascularization, highlighting its role in both normal and abnormal blood vessel growth.
Area of Science:
- Molecular Biology
- Developmental Biology
- Cell Biology
Background:
- Angiogenesis is regulated by vascular endothelial growth factor and Notch signaling.
- The role of microRNAs in angiogenesis is not well understood.
- MicroRNAs are small non-coding RNAs that regulate gene expression.
Purpose of the Study:
- To investigate the role of microRNA-155 (miR-155) in angiogenesis.
- To determine how miR-155 affects neovascularization and related cellular processes.
- To elucidate the molecular mechanisms by which miR-155 regulates angiogenesis.
Main Methods:
- Mouse retina angiogenesis model.
- In vitro cell assays.
- miR-155 mimics and antimiR-155 treatments.
- Analysis of Notch signaling pathway components and Smad1/5 expression.
Main Results:
- AntimiR-155 altered neovascularization in vivo.
- Endogenous miR-155 is involved in podosome formation, proteolysis, and cell migration, but not morphogenesis.
- miR-155 overexpression promoted hypersprouting and phenocopied Notch deficiency.
- miR-155 overexpression reduced Notch signaling by decreasing Smad1/5 expression, impairing tip cell invasive capacity and morphogenesis.
Conclusions:
- miR-155 is a novel regulator of physiological angiogenesis.
- miR-155 plays a role in pathological angiogenesis.
- Modulating miR-155 levels could offer therapeutic strategies for angiogenesis-related disorders.
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