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Finetti et al. Vessel Plus 2021;5:29 https://dx.doi.org/10.20517/2574-1209.2021.49 Page 7 of 9

In the light of the above reported data, CCM proteins appear to be key regulators of angiogenesis. The
capability to promote endothelial cell proliferation and migration, pseudocapillary formation, and activation
of angiogenic signal, may be consistent with the new evidence of the presence of mosaicism in CCM
vascular lesions. Loss of one of CCM genes appears sufficient to promote endothelial cell mobilization
through autocrine and paracrine mechanisms of action [Figure 2].

CONCLUSIONS
In this manuscript we overviewed the very recent advances in understanding the molecular and cellular
mechanisms underlying the onset and progression of CCM disease. In the last few years new experimental
evidences proposed a new perspective in the study of CCM and a new model for the CCM lesions formation
and development. According to these recent studies vascular lesions appear to be composed by a mosaicism
of mutated and non-mutated endothelial cells, in which mutated cells, with high angiogenic features,
promote the activation of non-mutated endothelial cells that move from quiescent to active state. CCM
mutated cells become able to secrete angiogenic factors and to reduce the production of antiangiogenic
factors, thus creating an imbalance between pro- and anti-angiogenic molecules that induces the formation
of a new defective vascular network.

Despite the few numbers of papers published so far, the data are robust and very promising. Deeper studies
on the mechanisms at the basis of mosaicism observed in CCM will lead to the identification of molecular
mediators and signaling pathways that contribute to the recruitment of non-mutated endothelial cells into
growing vascular network forming the cavernoma. These findings will permit to identify new targets for the
development of novel therapies or for evaluating drug repurposing aimed to prevent CCM onset and
progression. The possibility of designing therapeutic approaches aimed both at preventing growth of
mutated cells and recruitment of non-mutated cells will represent the new era for the treatment of CCM.

DECLARATIONS
Authors’ contributions
Made substantial contributions to conception and design of the study and performed data analysis and
interpretation: Finetti F, Trabalzini L

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by MIUR (Progetto Dipartimento di Eccellenza 2018-2022).

Conflicts of interest
Both authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2021.