RESUMO
BACKGROUND: Women with normotensive pregnancy are at a reduced risk of developing cardiovascular disease postpartum compared with those who experience hypertensive conditions during pregnancy. However, the underlying mechanisms remain poorly understood. During normotensive pregnancy, vast numbers of placental extracellular vesicles are released into the maternal circulation, which protect endothelial cells from activation and alter maternal vascular tone. We hypothesized that placental extracellular vesicles play a mechanistic role in lowering the risk of cardiovascular disease following normotensive pregnancy. OBJECTIVE: This study aimed to investigate the long-term effects of placental extracellular vesicles derived from normotensive term placentae on the cardiovascular system and explore the mechanisms underlying their biological effects. STUDY DESIGN: Spontaneously hypertensive rats were injected with placental extracellular vesicles from normotensive term pregnancies (2 mg/kg each time, n=8) or vehicle control (n=9) at 3 months of age. Blood pressure and cardiac function were regularly monitored from 3 months to 15 months of age. The response of mesenteric resistance arteries to vasoactive substances was investigated to evaluate vascular function. Cardiac remodeling, small artery remodeling, and renal function were investigated to comprehensively assess the impact of placental extracellular vesicles on cardiovascular and renal health. RESULTS: Compared with vehicle-treated control animals, rats treated with normotensive placental extracellular vesicles exhibited a significantly lower increase in blood pressure and improved cardiac function. Furthermore, the vasodilator response to the endothelium-dependent agonist acetylcholine was significantly enhanced in the normotensive placental extracellular vesicle-treated spontaneously hypertensive rats compared with the control. Moreover, treatment with placental extracellular vesicles reduced wall thickening of small renal vessels and attenuated renal fibrosis. CONCLUSION: Placental extracellular vesicles from normotensive term pregnancies have long-lasting protective effects reducing hypertension and mitigating cardiovascular damage in vivo.
RESUMO
Placental extracellular vesicles (EVs) have increasingly been recognized as a major mediator of feto-maternal communication. However, the cellular and molecular mechanisms of the uptake of placental EVs by recipient cells are still not well-understood. We previously reported that placental EVs target a limited number of organs in vivo. In the current study, we investigated the mechanisms underlying the uptake of placental EVs into target cells. Placental EVs were derived from explant cultures of normal or preeclamptic placentae. The mechanisms underlying the uptake of placental EVs were elucidated, using the phagocytosis or endocytosis inhibitor, trypsin-treatment or integrin-blocking peptides. The endothelial cell activation was studied using the monocyte adhesion assay after the preeclamptic EVs exposure, with and/or without treatment with the integrin blocking peptide, YIGSR. The cellular mechanism of the uptake of the placental EVs was time, concentration and energy-dependent and both the phagocytosis and endocytosis were involved in this process. Additionally, proteins on the surface of the placental EVs, including integrins, were involved in the EV uptake process. Furthermore, inhibiting the uptake of preeclamptic EVs with YIGSR, reduced the endothelial cell activation. The interaction between the placental EVs and the recipient cells is mediated by integrins, and the cellular uptake is mediated by a combination of both phagocytosis and endocytosis.
Assuntos
Vesículas Extracelulares , Pré-Eclâmpsia , Doenças Vasculares , Humanos , Feminino , Gravidez , Placenta/metabolismo , Células Endoteliais/metabolismo , Pré-Eclâmpsia/metabolismo , Vesículas Extracelulares/metabolismo , Doenças Vasculares/metabolismo , Integrinas/metabolismoAssuntos
Vesículas Extracelulares , Placenta , Feminino , Humanos , Gravidez , Pré-Eclâmpsia/prevenção & controleRESUMO
High-mobility group AT-hook1 (HMGA1, formerly HMG-I/Y), an architectural transcription factor, participates in a number of tumor biological processes. However, its effect on cervical cancer remains largely indistinct. In this study, we found that HMGA1 was generally overexpressed in cervical cancer tissues and was positively correlated with lymph node metastasis and advanced clinical stage. Via exogenously increasing or decreasing the expression of HMGA1, we showed that HMGA1 affected the proliferation, colony formation, migration and invasion of cervical cancer cells in vitro. Rescue experiments suggested that miR-221/222 could partly reverse HMGA1-mediated migration and invasion processes. Mechanistically, we discovered that HMGA1 accelerated the G1/S phase transition by regulating the expression of cyclin D1 and cyclin E1, which was consistent with the results of the in vivo experiment. Furthermore, we found that HMGA1 regulated the expression of the miR-221/222 cluster at the transcriptional level and that miR-221/222 targeted the 3'UTR of tissue inhibitor of metalloproteinases 3(TIMP3). We propose a fresh perspective that HMGA1 participates in the migration and invasion process via the miR-221/222-TIMP3-MMP2/MMP9 axis in cervical cancer. In summary, our study identified a critical role played by HMGA1 in the progression of cervical cancer and the potential mechanisms by which exerts its effects, suggesting that targeting HMGA1-related pathways could be conducive to the therapies for cervical cancer.
Assuntos
Ciclo Celular/genética , Movimento Celular/genética , Proteína HMGA1a/metabolismo , MicroRNAs/metabolismo , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Sequência de Bases , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Clonais , Ciclina D1/metabolismo , Ciclina E/metabolismo , Epitélio/metabolismo , Epitélio/patologia , Feminino , Fase G1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinases da Matriz/metabolismo , MicroRNAs/genética , Pessoa de Meia-Idade , Modelos Biológicos , Invasividade Neoplásica , Fase S/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismo , Ensaio Tumoral de Célula-TroncoRESUMO
Accessory spleen (AS) usually presents as an isolated asymptomatic mass of splenic tissue separated from the body of the actual spleen. Multiple pelvic ASs are more unusual than single pelvic AS. The present study reported on the rare case of multiple pelvic AS. A 39-year-old Chinese woman presented at our hospital with complaints of abdominal pain for one week. A large pelvic mass behind the uterus was identified on ultrasound examination. Multiple AS in the pelvis was primarily considered during the operation and confirmed by histopathological examination after the surgery. The literature in English language was also reviewed by retrieving studies on AS published over the past 30 years, and it was discussed how to diagnose and treat pelvic AS. In conclusion, to the best of our knowledge, the present study provided the first case report of multiple pelvic AS. The gynecologist should be aware of the rare possibility of an AS in patients with abdominal and pelvic complaints and/or a pelvic mass. Pelvic AS is generally determined during radiological investigations or during open or laparoscopic surgeries.