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Post-transcriptional regulation of angiogenesis.



 

Our group investigates the role of AS during angiogenesis, a highly regulated process resulting in the formation of new blood vessels from pre-existing capillaries. Angiogenesis has a crucial role in tumor growth by allowing oxygen and nutrients to reach proliferating cancer cells. Moreover, targeting tumor angiogenesis is considered a promising anti-cancer therapeutic approach. However, all attempted strategies so far have shown modest therapeutic effects. Indeed, tumor angiogenesis is a much more complex phenomenon than previously anticipated. Thus, a better understanding of the mechanisms sustaining growth of tumor vessels will be crucial to make anti-angiogenic therapies more efficient.

Recent studies have highlighted significant anatomic, structural and molecular similarities between the vascular and the nervous systems. Both systems possess specialized structures that, through filopodial extensions, probe the environment for guidance cues. Molecules regulating these processes have been termed "angioneurins". Since blood vessels and nerves are functionally interdependent, the malfunctioning of this 'neurovascular link' can lead to several vascular and neuronal disorders.

We found that the AS factor Nova2, which was previously considered to be neural cell-specific, is also expressed in endothelial cells (ECs) of blood vessels and plays an important role in vascular development. In particular, through gain- and loss-of-function approaches, we demonstrated that Nova2 regulates EC polarity and vascular lumen formation, fundamental steps in angiogenesis occurring during invasion and growth of the incipient vascular sprout. These defects are linked to AS changes of Nova2 target exons affecting Par polarity complex components and regulators. Consequently, vascular lumen formation defects are developed in vivo by nova2 morpholino mediated knockdown or CRISPR-induced genetic mutation (Giampietro C et al., Nature Communications 2015).

Based on the fact that Nova2 affects both neural and vascular cell processes, we propose Nova2 as a novel member of the "angioneurins" family. Interestingly, Nova2 is the only angioneurin that functions as post-transcriptional regulator of gene expression.

 

Our future aims are to:

1) Identify novel Nova2 targets in ECs;

2) Characterize the functional relevance of Nova2-mediated AS transcripts in angiogenesis;

3) Study the role of Nova2 in tumor vasculature.

 

 

 


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