An Alternative Role of C1q in Cell Migration and Tissue Remodeling: Contribution to Trophoblast Invasion and Placental Development

Agostinis, Chiara; Bulla, Roberta; Tripodo, Claudio; Gismondi, Angela; Stabile, Helena; Bossi, Fleur; Guarnotta, Carla; Garlanda, Cecília; Seta, Francesco De; Spessotto, Paola; Santoni, Angela; Ghebrehiwet, Berhane; Girardi, Guillermina; Tedesco, Francesco

doi:10.4049/jimmunol.0903215

Cited by 137 publications

(154 citation statements)

References 66 publications

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“…9 Thus, we hypothesized that mice deficient in C1q could develop PE. Indeed, we demonstrated an association among the absence of C1q, abnormal placentation, and onset of PE in mice.…”

Section: Discussionmentioning

confidence: 99%

“…8,9 In addition, we demonstrated previously that C1q deficiency was associated with impaired labyrinth development and decidual vessel remodeling and increased fetal death in mice. 9 These results suggest that defective local production of C1q may be involved in PE. 8,9 Indeed, here we demonstrate that pregnant C1q-deficient (C1q Ϫ/Ϫ ) mice recapitulate the key features of human PE: hypertension, albuminuria, endotheliosis, and increased levels of soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1) that correlate with increased fetal death and diminished litter size.…”

mentioning

confidence: 88%

“…C1q is widely distributed in human decidual stroma and is actively synthesized by migrating extravillous trophoblasts. 8,9 In addition, we demonstrated previously that C1q deficiency was associated with impaired labyrinth development and decidual vessel remodeling and increased fetal death in mice. 9 These results suggest that defective local production of C1q may be involved in PE.…”

mentioning

confidence: 88%

“…9 These results suggest that defective local production of C1q may be involved in PE. 8,9 Indeed, here we demonstrate that pregnant C1q-deficient (C1q Ϫ/Ϫ ) mice recapitulate the key features of human PE: hypertension, albuminuria, endotheliosis, and increased levels of soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1) that correlate with increased fetal death and diminished litter size.Despite advances in the understanding of the disorder, therapeutic approaches to the treatment of PE are severely limited. In the last few years, several studies in animals support the use of statins to prevent PE.…”

mentioning

confidence: 90%

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Role of Complement Component C1q in the Onset of Preeclampsia in Mice

2011

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Abstract-Preeclampsia (PE) is a life-threatening, pregnancy-induced disease and a leading cause of maternal and fetal morbidity and mortality. Despite considerable research, the causes of PE remain unclear, and there is no effective treatment. Studies in animal models that resemble this complex pregnancy-related disorder may help to identify possible therapies for PE. Complement component C1q has an important role in trophoblast migration, spiral arteries remodeling, and normal placentation. Here we show that pregnant C1q-deficient (C1q Ϫ/Ϫ ) mice recapitulate the key features of human PE: hypertension, albuminuria, endotheliosis, decreased placental vascular endothelial growth factor (VEGF) and elevated levels of soluble VEGF receptor 1 (sFlt-1) that correlate with increased fetal death. In addition, decreased blood flow and increased oxidative stress are observed in placentas from C1q Ϫ/Ϫ mice. Treatment of C1q Ϫ/Ϫ mice with pravastatin restored trophoblast invasiveness, placental blood flow, and angiogenic balance and, thus, prevented the onset of PE. Serum-soluble receptors for VEGF-1 levels were reduced and placental VEGF levels were significantly increased in C1q Ϫ/Ϫ mice treated with pravastatin compared with untreated C1q Ϫ/Ϫ mice (VEGF: 1067Ϯ171 versus 419Ϯ194 pg/mL; PϽ0.01). Pravastatin treatment reduced hypertension (change in mean arterial pressure: 1Ϯ1 versus 18Ϯ3 mm Hg in C1q Ϫ/Ϫ untreated mice), and albuminuria (of creatinine) was reduced from 820Ϯ175 to 117Ϯ45 g/mg (both PϽ0.01). Renal damage and endothelial dysfunction were significantly attenuated with pravastatin. This model that highlights the causative role of impaired trophoblast invasion in the pathogenesis of PE allowed us to identify pravastatin as a good therapeutic option to prevent PE. Key Words: mouse model Ⅲ preeclampsia Ⅲ trophoblast invasion Ⅲ complement Ⅲ pravastatin P reeclampsia (PE), a pregnancy-specific, multisystemic disorder, is a leading cause of maternal and perinatal mortality and morbidity. 1 Because PE only occurs during pregnancy and its symptoms resolve after delivery, the placenta is thought to be crucial to the development of the disease. Indeed, several studies suggested that a defective trophoblast invasion and abnormal placentation are some of the underlying mechanisms of PE. 2,3 Conversion of the maternal spiral arteries into larger competent vessels is one of the essential steps in the development of the normal placenta. This process is apparently dependent on the invasion by trophoblasts of the subendometrial area and the spiral arteries. PE is characterized by shallow trophoblast invasion and unconverted narrow spiral arteries that leads to placental dysfunction and endothelial injury that eventually manifest as maternal hypertension and proteinuria. 4 The study of PE in women is of critical importance; however, studies in humans have obvious limitations that prevent investigation of many pathophysiological mechanisms and that often limit the ability to establish cause-andeffect relationships in pregnant...

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“…9 Thus, we hypothesized that mice deficient in C1q could develop PE. Indeed, we demonstrated an association among the absence of C1q, abnormal placentation, and onset of PE in mice.…”

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 88%

mentioning

confidence: 88%

mentioning

confidence: 90%

See 2 more Smart Citations

Role of Complement Component C1q in the Onset of Preeclampsia in Mice

2011

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“…C1q is preferentially, if not exclusively (41), produced by DCs and macrophages. The finding that PU.1 and IRF8 play key roles in the regulation of C1q gene expression help explain DC and macrophage production of C1q.…”

Section: Discussionmentioning

confidence: 99%