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Etude du rôle et du mécanisme d’action de deux peptides vasoactifs, l’urotensine II et l’urotensin II-related peptide sur la fonction astrocytaire

Abstract : Urotensin II (UII) and its paralog urotensin II-related peptide (URP) are two cyclic neuropeptides considered as the most potent endogenic vasoactive factors characterized so far. UII and URP interact with the UT receptor, classically coupled to a phospholipase C. Peripheral effects of both UII and URP, especially in the cardiovascular system, are well characterized. In contrast, the role in the central nervous system remains unclear. UT is strongly expressed in motoneurons from the spinal cord, but also in a subpopulation of astrocytes localized in some brain areas such as hippocampus and thalamus. Several groups showed that UII exhibits mitogenic effect on UT-transfected cells as well as on native cells which naturally express the receptor. The UII and UT expression has been reported in different tumoral cell lines, including ones derived from glioblastoma. In vivo, astrocyte proliferation is observed during cerebral ontogenesis, neurodegenerative diseases and brain tumorigenesis. Taken together, these data led us to examine the role of UII and URP in astroglial activity in physiological and pathophysiological conditions. This project aimed at i) characterizing UII and URP binding sites expressed by astrocytes and determining the transduction pathways involved, ii) testing a potent peptidic antagonist of UT in our model and iii) investigating a putative role of UII in pathologies associated with astrocyte proliferation. Several complementary methods allowed us to find the presence of mRNA encoding UT (RT-PCR), and of its protein (western blot, flow cytometry) in cultured rat cortical astrocytes. UII interacts with a very high- and high-affinity binding sites coupled to a phospholipase C whereas URP binds a single receptor. Both peptides stimulate the polyphosphoinositide (PIP) metabolism. Only very high-affinity binding and UII-induced PIP metabolism increase are sensitive to pertussis toxin (PTX), a specific Gi/Go protein blocker. Both UII and URP evoked a dose-dependent [Ca2+]c elevation with an acute phase following by a plateau. However, sole the UII dose-response curve is biphasic with a biological activity observed at very low concentrations (10-11 M). Astrocyte response to UII and URP is abolished in the presence of U73122, a phospholipase C inhibitor, and the specific blockade of IP3 receptor-channels by 2-APB strongly reduced both the peak and the plateau. Extracellular calcium chelation by EGTA partially inhibited the first phase and suppressed the plateau. The use of specific calcium channel blockers showed that the calcium influx mostly involves T-type channels. These results indicate that both UII and URP, by activating UT expressed by astrocytes, recruite calcium from intra- and extracellular pools via T-type channels. Researchers from the lab designed several UII and URP analogs, such as [D-Trp4]URP, [Orn5]URP and [D-Tyr6]URP, which are able to block spasmogenic effects of UII on rat aortic rings. Administered in the vinicity of astrocytes, [D-Trp4]URP and [D-Tyr6]URP provoke a [Ca2+]c increase similar to that observed with URP, whereas [Orn5]URP is devoid of any intrinsic activity. This compound induced a dose-dependent inhibition of the calcium mobilization evoked by both UII and URP, with rightward-shift of the dose-response curves accompanied by a decrease of efficiency. These results are the first characterization of a potent urotensinergic antagonist in a nervous native model, suggesting that [Orn5]URP is an interesting tool for the development of new selective UT antagonists. The last part of my Ph.D work concerns the study of the potential role of urotensinergic system on astrocyte proliferation and astroglial tumor development. Our results showed that only the application of graded concentrations of UII on astrocytes increases cell density. In collaboration with Pr L’Houcine Ouafik (EMI-0359, Marseille), we measured mRNA levels of UII, URP and UT in tumoral cell lines, xenografts and human glioblastoma extracts. The four tumoral cell lines tested, derived from astrocytoma (SW1088 and SW1783) and glioblastoma (U87 and U138), express the genes encoding UII, URP and UT. A xenograft, resulting the U87 cell injection in Nude mice, exhibits much greater levels of UII and UT mRNA than ones measured from cultured cell lines. However, all human glioblastoma samples tested expressed UII, URP and UT mRNA. Nevertheless, statistical analysis of our data revealed that only the UII and the UT gene expression levels are positively correlated. These results strongly suggest that the urotensinergic system may play an important role in the control of glial tumorigenesis. Taken together, these data indicate that, despite of their structural analogies, UII and URP do not strictly share the same pharmacological profile and may exert distinct physiological functions. In particular, UII might be involved in the control of cell proliferation, especially during tumorigenesis of glial cells. This work opens some new perspectives for astroglial tumor treatment.
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Mickael Diallo. Etude du rôle et du mécanisme d’action de deux peptides vasoactifs, l’urotensine II et l’urotensin II-related peptide sur la fonction astrocytaire. Sciences du Vivant [q-bio]. Université de Rouen, France, 2009. Français. ⟨tel-02417037⟩



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