Angiogenesis is the process by which sprouting blood vessels coordinately grow in tissues, in order to provide each cell with the appropriate amount of oxygen and nutrient and with the capability to dispose of cellular waste. Angiogenesis is a normal and essential process in development, as well as in wound healing and tissue regeneration, and in the transition of tumors from a benign state to a malignant one. Therefore, understanding the basic mechanisms that control this essential process, has far-reaching implications in developmental biology and in the management of human disease.
Endothelial cells (EC) are the major players of angiogenesis. Extensive evidence reveals that ECs controls angiogenesis integrating multiple signaling and metabolic pathways, which lead to appropriate, rapid and localized responses. The unique combination of tridimensional extracellular signals and metabolites interplays with the developmental potential of ECs leading to the proper formation of a vascular bead. The modulation of gene expression in ECs is crucial for their function.
Translation, originally held as a passive decoding of transcribed mRNAs, has been recently found to act as a powerful modulator of gene expression. Translational activation, by which proteins are timely synthesized from pre-existing mRNAs, offers to ECs the possibility to rapidly modulate their proteome in response to external stimuli. In this context, our laboratories have provided unpublished and published evidence that: a) the expression of angiogenesis regulators, such as VEGF and VEGFR2, is controlled at the translational level, b) local clues driven by extracellular signals, e.g. secreted semaphorin 3A (SEMA3A), activate in a spatially restricted form, signaling pathways converging on translation, and c) metabolic clues, such as intracellular glutamine synthesis, reshape the proteome of ECs. Based on these data, we hypothesize that the complex hierarchical branching of the mature and functional vascular system is regulated at the translational level, integrating the positioning of signaling endosomes and the specific localization of mRNAs through regulatory cascades that include glutamine metabolism and SEMA3A-elicited pathways.
Our network is composed by three major Italian experts individually contributing a leading expertise on translational control of cellular and animal models, on the process of angiogenesis during development and pathology, and on the guidance molecules that control the proper morphogenesis and function of vascular networks. Combining our skills, we have built on our preliminary data a pipeline that aims at a) understanding the crosstalk between guidance cues and glutaminolysis in the control of endothelial cell function; b) how this crosstalk activates local translation during developmental and pathological angiogenesis, and c) the contribution of specific signaling pathways on the shaping of localized and specific translation.
Endothelial cells (EC) are the major players of angiogenesis. Extensive evidence reveals that ECs controls angiogenesis integrating multiple signaling and metabolic pathways, which lead to appropriate, rapid and localized responses. The unique combination of tridimensional extracellular signals and metabolites interplays with the developmental potential of ECs leading to the proper formation of a vascular bead. The modulation of gene expression in ECs is crucial for their function.
Translation, originally held as a passive decoding of transcribed mRNAs, has been recently found to act as a powerful modulator of gene expression. Translational activation, by which proteins are timely synthesized from pre-existing mRNAs, offers to ECs the possibility to rapidly modulate their proteome in response to external stimuli. In this context, our laboratories have provided unpublished and published evidence that: a) the expression of angiogenesis regulators, such as VEGF and VEGFR2, is controlled at the translational level, b) local clues driven by extracellular signals, e.g. secreted semaphorin 3A (SEMA3A), activate in a spatially restricted form, signaling pathways converging on translation, and c) metabolic clues, such as intracellular glutamine synthesis, reshape the proteome of ECs. Based on these data, we hypothesize that the complex hierarchical branching of the mature and functional vascular system is regulated at the translational level, integrating the positioning of signaling endosomes and the specific localization of mRNAs through regulatory cascades that include glutamine metabolism and SEMA3A-elicited pathways.
Our network is composed by three major Italian experts individually contributing a leading expertise on translational control of cellular and animal models, on the process of angiogenesis during development and pathology, and on the guidance molecules that control the proper morphogenesis and function of vascular networks. Combining our skills, we have built on our preliminary data a pipeline that aims at a) understanding the crosstalk between guidance cues and glutaminolysis in the control of endothelial cell function; b) how this crosstalk activates local translation during developmental and pathological angiogenesis, and c) the contribution of specific signaling pathways on the shaping of localized and specific translation.