Role of PI3K in pericytes during angiogenesis
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2018-06-09
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Pericytes (PCs) are important regulators of the vascular development
promoting vessel growth and stabilization. They have recently emerged as a
therapeutic target to promote or inhibit angiogenesis. Therefore, advancing our
basic understanding on PCs biology and its molecular regulators during
physiological angiogenesis is essential to develop PC-related therapies. One of
the major pathways leading to cellular proliferation, migration, and survival is
relayed by PI3K. Data from our laboratory and others have demonstrated
isoform selectivity stimulating PI3K signalling in the regulation of both, the ECs
and vSMCs. Interestingly, in these two cell populations’ p110α seems to be the
major isoform.
By using pharmacological and genetic tools together with cultured PCs
and retinal systems we have found that PCs pass through different states
during vessel development, and that PI3K signalling regulates these cells in an
isoform-specific manner. We have seen that immature and active PCs promote
vessel growth while, mature and quiescent PCs result in vascular stabilization
and remodelling. Moreover and unexpectedly, our results have identified p110β
as the key regulator of PCs proliferation and growth. Inactivation of p110β in
PCs, but not p110α, results in PC proliferation arrest and in several
morphological changes, which resemble a more mature PC. Lack of p110β in
PCs also leads to a more mature vascular plexus. We observed reduced vessel
density, EC proliferation arrest and increased deposition of collagen IV.
Furthermore, PTEN seems to be the regulator of PI3K in PCs, opposing the
p110β effects and, leading to a more mature and stable PC and subsequently
also more mature vasculature.
Since p110β-PI3K controls PC growth and proliferation, it suggests that
target therapy directed to p110β in cancer could affect PCs. Using a pancreatic
neuroendocrine tumour mouse model (RIP1-Tag2) we have seen that
pharmacological inhibition of p110β impacts on tumour progression and in PCs
growth. However, it also results in a slight reduction in the overall survival of the
animal, without affecting their metastatic potential. Therefore, other studies are
needed to further investigate p110β as a possible PC-specific target therapy.
Descrição
Memòria presentada per Ana Raquel Martins Figueiredo per optar al títol de doctora per la Universitat de Barcelona