Role of PI3K in pericytes during angiogenesis

Abstract

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.