Mechanisms of vascular dysfunction in the interleukin-10-deficient murine model of preeclampsia indicate nitric oxide dysregulation.
Mechanisms of vascular dysfunction in the interleukin-10-deficient murine model of preeclampsia indicate nitric oxide dysregulation.
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子痫前期白细胞介素 - 10 缺陷小鼠模型中血管功能障碍的机制表明存在一氧化氮调节异常。
DOI：
10.1016/j.kint.2020.09.034
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发表时间：
2021-03
影响因子：
19.6
通讯作者：
Garovic VD
中科院分区：
文献类型：
--
作者：
Cubro H;Nath KA;Suvakov S;Garcia-Valencia O;Parashuram S;White WM;Weissgerber TL;Nath MC;Milic NM;Sontag F;d'Uscio LV;Zhu Y;Kirkland JL;Tchkonia T;Alexander MP;Quinton RA;Katusic ZS;Grande JP;Garovic VD
子痫前期是一种妊娠期特有的高血压疾病，其特征为蛋白尿以及妊娠后半期的血管损伤。我们假设，基于将人类子痫前期血清注入白细胞介素 - 10基因敲除（IL - 10−/− ）小鼠所构建的子痫前期小鼠模型中存在内皮依赖性血管功能障碍，并对血管损伤的潜在机制展开研究。在妊娠期，给怀孕的野生型和IL - 10−/− 小鼠注射血压正常者或重度子痫前期患者（sPE）的血清。通过测量血压、评估蛋白尿、检测血管生成因子、观察肾切片中足突消失和内皮细胞增生情况，以及检测注射sPE血清的IL - 10−/− 小鼠（IL - 10−/−sPE）胎盘中糖原的积累，来确认子痫前期样表型。对分离出的主动脉血管舒缩功能进行评估。与野生型血压正常小鼠相比，IL - 10−/−sPE小鼠模型对去氧肾上腺素的主动脉收缩反应显著增强，且内皮依赖性舒张功能受损，内皮非依赖性舒张功能也有一定程度受损。用环氧化酶抑制剂吲哚美辛处理分离出的主动脉，可改善但无法使对去氧肾上腺素的收缩反应恢复至野生型血压正常小鼠的水平，这表明一氧化氮下调以及吲哚美辛抵抗性血管收缩因子也起到了作用。相比之下，吲哚美辛可使IL - 10−/−sPE小鼠主动脉的舒张功能恢复正常。因此，我们的研究结果明确了在IL - 10−/−sPE子痫前期小鼠模型中，IL - 10缺乏在环氧化酶途径失调和血管功能障碍中的作用，并指出一氧化氮调节异常可能也有一定影响。这些化合物及相关机制可能成为子痫前期预防和治疗策略中的诊断标志物和治疗靶点。
结论：
IL - 10缺乏的子痫前期小鼠模型与血管反应性功能障碍相关，这是由于环氧化酶途径失调所致，一氧化氮下调可能也起到了一定作用。
Preeclampsia is a pregnancy-specific hypertensive disorder characterized by proteinuria, and vascular injury in the second half of pregnancy. We hypothesized that endothelium-dependent vascular dysfunction is present in a murine model of preeclampsia based on administration of human preeclamptic sera to interleukin −10−/− mice and studied mechanisms that underlie vascular injury. Pregnant wild type and IL-10−/− mice were injected with either normotensive or severe preeclamptic patient sera (sPE) during gestation. A preeclampsia-like phenotype was confirmed by blood pressure measurements; assessment of albuminuria; measurement of angiogenic factors; demonstration of foot process effacement and endotheliosis in kidney sections; and by accumulation of glycogen in placentas from IL-10−/− mice injected with sPE sera (IL-10−/−sPE). Vasomotor function of isolated aortas was assessed. The IL-10−/−sPE murine model demonstrated significantly augmented aortic contractions to phenylephrine and both impaired endothelium-dependent and, to a lesser extent, endothelium-independent relaxation compared to wild type normotensive mice. Treatment of isolated aortas with indomethacin, a cyclooxygenase inhibitor, improved, but failed to normalize contraction to phenylephrine to that of wild type normotensive mice, suggesting the additional contribution from nitric oxide downregulation and effects of indomethacin-resistant vasoconstricting factors. In contrast, indomethacin normalized relaxation of aortas derived from IL-10−/−sPE mice. Thus, our results identify the role of IL-10 deficiency in dysregulation of the cyclooxygenase pathway and vascular dysfunction in the IL-10−/−sPE murine model of preeclampsia, and point towards a possible contribution of nitric oxide dysregulation. These compounds and related mechanisms may serve both as diagnostic markers and therapeutic targets for preventive and treatment strategies in preeclampsia. CONCLUSION: IL-10 deficient murine model of preeclampsia is associated with vascular reactivity dysfunction, due to dysregulation in cyclooxygenase pathway, with a possible role of NO downregulation.
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DOI：
10.1152/ajpheart.01234.2004
发表时间：
2005-08-01
影响因子：
4.8
作者：
Gunnett, CA;Lund, DD;Heistad, DD
通讯作者：
Heistad, DD
DOI：
10.1161/hypertensionaha.113.01648
发表时间：
2013-11
期刊：
Hypertension (Dallas, Tex. : 1979)
影响因子：
--
作者：
Brewer J;Liu R;Lu Y;Scott J;Wallace K;Wallukat G;Moseley J;Herse F;Dechend R;Martin JN Jr;Lamarca B
通讯作者：
Lamarca B
影响因子：
6.1
作者：
Lima, Victor V.;Zemse, Saiprasad M.;Giachini, Fernanda R.
通讯作者：
Giachini, Fernanda R.
影响因子：
15.9
作者：
GANT, NF;DALEY, GL;MACDONALD, PC
通讯作者：
MACDONALD, PC
DOI：
10.1152/ajpheart.2000.279.4.h1555
发表时间：
2000-10-01
影响因子：
4.8
作者：
Gunnett, CA;Heistad, DD;Faraci, FM
通讯作者：
Faraci, FM