Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital and Harvard Medical School , Boston, Massachusetts.
Am J Physiol Heart Circ Physiol. 2018 Jul 1;315(1):H33-H47. doi: 10.1152/ajpheart.00045.2018. Epub 2018 Mar 23.
Preeclampsia is a complication of pregnancy manifested as maternal hypertension (HTN) and fetal intrauterine growth restriction, with unclear mechanisms. Placental ischemia increases antiangiogenic soluble fms-like tyrosine kinase-1 (sFlt-1) relative to angiogenic placental growth factor (PlGF); however, the molecular targets are unclear. To test the hypothesis that placental ischemia-induced changes in sFlt-1 and PlGF target vascular and uteroplacental matrix metalloproteinases (MMPs), we tested whether raising the sFlt-1-to-PlGF ratio by infusing sFlt-1 (10 µg·kg·day) in pregnant (Preg) rats increases blood pressure (BP) and alters MMPs and whether correcting sFlt-1/PlGF by infusing PlGF (20 µg·kg·day) in Preg rats with reduced uterine perfusion pressure (RUPP) improves BP and reverses the changes in MMPs. On gestational day 19, BP was higher and the litter size and uterine, placenta, and pup weight were less in Preg + sFlt-1 and RUPP than Preg rats and restored in RUPP + PlGF versus RUPP rats. Gelatin and casein zymography and Western blots revealed decreases in MMP-2 and MMP-9 and increases in MMP-1 and MMP-7 in the aorta, uterine artery, uterus, and placenta of Preg + sFlt-1 and RUPP versus Preg rats, which were reversed in RUPP + PlGF versus RUPP rats. Collagen types I and IV were more abundant in Preg + sFlt-1 and RUPP versus Preg rats and were reversed in RUPP + PlGF versus RUPP rats. Thus, PlGF reverses decreased vascular and uteroplacental MMP-2 and MMP-9 and increased MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and sFlt-1 in HTN in pregnancy. Angiogenic factors and MMP modulators could rectify changes in MMPs and collagen, restore vascular and uteroplacental remodeling, and improve HTN and intrauterine growth restriction in preeclampsia. NEW & NOTEWORTHY Understanding the mechanisms of preeclampsia could help in its prevention and management. This study shows that correcting soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) imbalance by infusing PlGF reverses the decreases in vascular and uteroplacental matrix metalloproteinase (MMP)-2 and MMP-9 and the increases in MMP-1, MMP-7, and collagen types I and IV induced by placental ischemia and antiangiogenic sFlt-1 in hypertension in pregnancy. Angiogenic factors and MMP modulators could rectify changes in vascular and uteroplacental MMPs and collagen content and ameliorate hypertension and intrauterine growth restriction in preeclampsia.
子痫前期是一种妊娠并发症，表现为母体高血压 (HTN) 和胎儿宫内生长受限，其机制尚不清楚。胎盘缺血会增加抗血管生成的可溶性 fms 样酪氨酸激酶-1 (sFlt-1) 与血管生成胎盘生长因子 (PlGF) 的比值;然而，分子靶点尚不清楚。为了验证胎盘缺血引起的 sFlt-1 和 PlGF 靶血管和胎盘基质金属蛋白酶 (MMPs) 变化的假设，我们检测了在怀孕 (Preg) 大鼠中输注 sFlt-1(10 µg·kg·day) 以提高 sFlt-1/PlGF 比值是否会增加血压 (BP) 并改变 MMPs，以及在 RUPP 大鼠中输注 PlGF(20 µg·kg·day) 以纠正 sFlt-1/PlGF 是否会改善 BP 并逆转 MMPs 的变化。在妊娠第 19 天，与 Preg 大鼠相比，Preg + sFlt-1 和 RUPP 大鼠的血压升高，胎仔数和子宫、胎盘和幼仔体重减少，而 RUPP + PlGF 大鼠的血压升高和胎仔数和子宫、胎盘和幼仔体重恢复正常。明胶和酪蛋白酶谱和 Western blot 显示，与 Preg 大鼠相比，Preg + sFlt-1 和 RUPP 大鼠的主动脉、子宫动脉、子宫和胎盘中的 MMP-2 和 MMP-9 减少，MMP-1 和 MMP-7 增加，而 RUPP + PlGF 大鼠则逆转了这一变化。与 Preg 大鼠相比，Preg + sFlt-1 和 RUPP 大鼠的胶原 I 型和 IV 型更丰富，而 RUPP + PlGF 大鼠则逆转了这一变化。因此，PlGF 逆转了由胎盘缺血和 sFlt-1 在妊娠高血压中引起的 MMP-2 和 MMP-9 的减少，以及 MMP-1、MMP-7 和胶原 I 型和 IV 型的增加。血管生成因子和 MMP 调节剂可以纠正 MMP 和胶原的变化，恢复血管和胎盘重塑，改善子痫前期的高血压和宫内生长受限。新的和值得注意的是：了解子痫前期的发病机制有助于预防和治疗。本研究表明，通过输注 PlGF 纠正可溶性 fms 样酪氨酸激酶-1 (sFlt-1)/胎盘生长因子 (PlGF) 失衡，可以逆转由胎盘缺血和抗血管生成 sFlt-1 引起的 MMP-2 和 MMP-9 减少，以及 MMP-1、MMP-7 和胶原 I 型和 IV 型在妊娠高血压中的增加。血管生成因子和 MMP 调节剂可以纠正血管和胎盘 MMPs 和胶原含量的变化，改善子痫前期的高血压和宫内生长受限。
