Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans.
Angiogenic growth factors are new and essential players in the sustained relaxin vasodilatory pathway in rodents and humans.
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DOI：
10.1161/hypertensionaha.110.165027
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发表时间：
2011-06
期刊：
影响因子：
--
通讯作者：
Conrad KP
中科院分区：
文献类型：
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作者：
McGuane JT;Danielson LA;Debrah JE;Rubin JP;Novak J;Conrad KP
松弛素正在成为一种重要的妊娠期血管扩张剂，并正在测试急性心力衰竭的后负荷减少。然而，松弛素诱导的血管舒张的机制还不完全清楚。本研究的目的是建立一种新的松弛素诱导的血管舒张的体外模型，并使用这种方法以及慢性仪器，清醒大鼠血管生成因子的松弛素血管舒张通路中的作用进行调查。在体外用重组人H2松弛素孵育大鼠和小鼠小肾动脉3小时可减弱肌源性收缩，这可被明胶酶、内皮素B受体和一氧化氮合酶抑制剂阻断。这些发现证实了从注入松弛素的非妊娠和中期妊娠大鼠中分离的动脉中的离体观察结果，从而验证了新的实验方法并使人类动脉研究成为可能。松弛素在体外孵育人皮下小动脉3小时也通过相同的分子中间体减弱肌源性收缩。血管内皮生长因子受体抑制剂SU 5416、三种不同的血管内皮生长因子和两种不同的胎盘生长因子中和抗体阻止松弛素减弱大鼠和小鼠小肾动脉和人皮下动脉的肌源性收缩。SU 5416给药还可预防慢性器械清醒大鼠中松弛素诱导的肾血管舒张和超滤。从这些大鼠中分离的小肾动脉显示松弛素灌注组中MMP-2活性增加，SU 5416不能阻止。我们的结论是，在大鼠，小鼠和人类的松弛素血管舒张机制是一致的，血管生成因子是新的和必要的中间体。
Relaxin is emerging as an important vasodilator of pregnancy, and is being tested for afterload reduction in acute heart failure. However, the mechanisms underlying relaxin-induced vasodilation are incompletely understood. The aims of this study were to establish a new in vitro model for relaxin-induced vasodilation, and to use this approach as well as chronically instrumented, conscious rats to investigate the role of angiogenic growth factors in the relaxin vasodilatory pathway. Incubation of rat and mouse small renal arteries with recombinant human H2 relaxin for 3hr in vitro attenuated myogenic constriction, which was blocked by inhibitors of gelatinases, the endothelin B receptor and nitric oxide synthase. These findings corroborate ex vivo observations in arteries isolated from relaxin-infused nonpregnant and midterm pregnant rats, thereby validating the new experimental approach and enabling study of human arteries. Incubation of small human subcutaneous arteries with relaxin for 3hr in vitro also attenuated myogenic constriction through the same molecular intermediates. Vascular endothelial growth factor receptor inhibitor SU5416, three different vascular endothelial growth factor and two different placental growth factor neutralizing antibodies prevented relaxin from attenuating myogenic constriction in rat and mouse small renal, and human subcutaneous arteries. SU5416 administration also prevented relaxin-induced renal vasodilation and hyperfiltration in chronically instrumented, conscious rats. Small renal arteries isolated from these rats demonstrated increased MMP-2 activity in the relaxin-infused group, which was not prevented by SU5416. We conclude that there is concordance of relaxin vasodilatory mechanisms in rats, mice and humans, and angiogenic growth factors are novel and essential intermediates.