Abstract
Angiogenesis requires the temporal coordination of the proliferation and the migration of endothelial cells. Here, we investigated the regulatory role of microRNAs (miRNAs) in harmonizing angiogenesis processes in a three-dimensional in vitro model. We described a microRNA network which contributes to the observed down- and upregulation of proliferative and migratory genes, respectively. Global analysis of miRNA-target gene interactions identified two sub-network modules, the first organized in upregulated miRNAs connected with downregulated target genes and the second with opposite features. miR-424-5p and miR-29a-3p were selected for the network validation. Gain- and loss-of-function approaches targeting these microRNAs impaired angiogenesis, suggesting that these modules are instrumental to the temporal coordination of endothelial migration and proliferation. Interestingly, miR-29a-3p and its targets belong to a selective biomarker that is able to identify colorectal cancer patients who are responding to anti-angiogenic treatments. Our results provide a view of higher-order interactions in angiogenesis that has potential to provide diagnostic and therapeutic insights.
Highlights
The expansion of a vascular network through the sprouting angiogenesis (SA) process requires a coordinated control of many cellular functions, including the activation of quiescent endothelial cells (ECs), cell protrusion, basal lamina and extracellular matrix degradation, cell migration and proliferation, deposition of new basement membrane, cell junctions and cell polarity alteration (Carmeliet and Jain, 2011)
We show that in the initial step of SA, miRNAs act cooperatively to give robustness to the specification of the tip cell phenotype by reducing the expression of genes that are associated with cell-cycle progression and of members of the mitogen-associated protein kinase (MAPK) cascade that sustains VEGF-A-mediated cell proliferation, while de-repressing genes that are involved in cell migration and extracellular matrix remodeling
To study the activation of quiescent endothelial cells induced by an angiogenic stimulus, and the impact that miRNAs may exert on this process, we exploited a three-dimensional (3D) model that mimics the initial phase of SA in vitro (Heiss et al, 2015; Nowak-Sliwinska et al, 2018)
Summary
The expansion of a vascular network through the sprouting angiogenesis (SA) process requires a coordinated control of many cellular functions, including the activation of quiescent endothelial cells (ECs), cell protrusion, basal lamina and extracellular matrix degradation, cell migration and proliferation, deposition of new basement membrane, cell junctions and cell polarity alteration (Carmeliet and Jain, 2011). In response to an angiogenic stimulus, activated ECs acquire distinct specialized phenotypes to accomplish these different tasks (Jakobsson et al, 2010), leading to the formation of a new functional vascular network. During SA, ECs dynamically switch from a tip phenotype, which guides the network expansion, to a stalk cell state that is characterized by active proliferation.
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