Abstract P104: Activation of Endoplasmic Reticulum Stress and Thrombospondin-1 Anti-Angiogenic Mechanisms in Placentas of Hypertensive Mice
| Autor: | Casandra Marc, Émilie Pepin, Allahnah Achille, Mariane Bertagnolli, Nozha Raguema, Julie L. Lavoie |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Hypertension. 74 |
| ISSN: | 1524-4563 0194-911X |
| Popis: | Background: Thrombospondin-1 (Thbs1) is an anti-angiogenic focal adhesion glycoprotein. It binds to receptors CD36, LRP1 and CD47 activating anti-proliferative and anti-migratory mechanisms. Pre-eclampsia (PE) is characterized by poor placenta perfusion and angiogenesis, which is stimulated by oxidant and endoplasmic reticulum (ER) stresses contributing to placental insufficiency. ER stress has also been linked to Thbs1 anti-angiogenic actions. However, whether this mechanism is active in PE is unclear. Our aim was to describe ER stress and Thbs1 regulation in placental tissues and endothelial cells in a genetic mice model of chronic maternal hypertension and superposed pre-eclampsia. Methods and Results: Placentas (n=8/group) were collected at 18.5 gestational days from transgenic mice overexpressing human renin and angiotensinogen versus controls (C57BL/6). CD31+ endothelial cells were isolated from placental tissues by magnetic separation. ER stress proteins IRE1a and calreticulin (CLR), as well as Thbs1 and receptors expressions were measured by western blot in placental tissues. CLR and Thbs1 localization in endothelial cells was assessed by immunofluorescence. Data are presented as average±SD. Our results show that IRE1a expression was increased in placentas of hypertensive mice (54±24% P=.05) while CLR was not different. However, in endothelial cells, CLR was shown mobilized from the ER compartment towards the membrane in cells of hypertensive pregnancies or in those exposed to hypoxia. Thbs1 (122±51% P=.03) and receptors CD47 (51±21% P=.03) and LRP1 (58±25% P=.04) were more expressed in placentas of hypertensive pregnancies versus controls, while CD36 was not different. The treatment of endothelial cells of hypertensive pregnancies with a Thbs1 inhibitor, LSKL, has significantly enhanced their angiogenic capacity allowing cells to form closed tubes on matrigel in comparison with the lack of closed tubes in untreated cells. Conclusion: Our results described an ER stress state and Thbs1 upregulation in placental tissue and endothelial cells of hypertensive pregnancy. Our findings suggest an important anti-angiogenic role of the Thbs1 mechanism in placentas of hypertensive mice. |
| Databáze: | OpenAIRE |
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