Lin Chen, Mazzuca Marc Q, Khalil Raouf A
Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
Vascular Surgery Research Laboratories, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, United States.
Biochem Pharmacol. 2024 Oct;228:116227. doi: 10.1016/j.bcp.2024.116227. Epub 2024 Apr 19.
Preeclampsia is a pregnancy-related disorder manifested as hypertensive pregnancy (HTN-Preg) and often fetal growth restriction (FGR), but the mechanisms involved are unclear. We have reported enhanced reactivity of systemic vessels in HTN-Preg rats, but the critical changes in the uterine circulation are less clear. We tested whether HTN-Preg involves localized aberrations in uterine arterial tone, stiffness and remodeling by matrix metalloproteinases (MMPs). Blood pressure (BP) and litter size were recorded in normal pregnant (Preg) rats and Preg rats with reduced uteroplacental perfusion pressure (RUPP). Isolated uterine arteries were placed in a pressure myograph for measuring intrinsic and extrinsic tone and arterial stiffness. Arteries were bathed in normal Krebs solution (2.5 mM Ca), Ca-free (2 mM EGTA) Krebs, treated with sodium nitroprusside (SNP), or endothelium denuded, then pressurized at 10 mmHg steps from 10 to 110 mmHg, and the % change in diameter was analyzed to measure total (active + passive), active Ca-dependent myogenic, passive, and endothelium-dependent tone, respectively. BP was higher and the litter size and pup weight were reduced in RUPP vs Preg rats. In normal Krebs, increasing intraluminal pressure caused smaller increments in diameter in arteries of RUPP vs Preg rats, suggesting greater total vascular tone. Arterial incubation in Ca-free Krebs, treatment with SNP or endothelium-removal abolished the differences in vascular tone, and subtraction of each of these components from total vascular tone revealed significant active Ca-dependent myogenic, passive, and endothelium-dependent tone, respectively, in RUPP vs Preg rats. The total and passive strain-stress curves were shifted leftward in arteries of RUPP vs Preg rats, indicating increased uterine arterial stiffness. Arterial sections showed decreased lumen/total and increased wall/total area, and immunohistochemistry revealed greater MMP-1 and MMP-7 staining particularly in the media, suggesting uterine arterial remodeling by MMPs in RUPP vs Preg rats. The increased uterine arterial active myogenic, passive, and endothelium-dependent tone, arterial stiffness and remodeling by MMPs would further reduce uterine blood flow and exacerbate uteroplacental ischemia, FGR and HTN-Preg.
子痫前期是一种与妊娠相关的疾病，表现为妊娠高血压（HTN-Preg），常伴有胎儿生长受限（FGR），但其涉及的机制尚不清楚。我们曾报道HTN-Preg大鼠全身血管反应性增强，但子宫循环的关键变化尚不太明确。我们测试了HTN-Preg是否涉及子宫动脉张力、僵硬度以及基质金属蛋白酶（MMPs）介导的重塑的局部异常。记录正常妊娠（Preg）大鼠和子宫胎盘灌注压降低（RUPP）的Preg大鼠的血压（BP）和产仔数。将分离的子宫动脉置于压力肌动描记仪中，以测量内在和外在张力以及动脉僵硬度。动脉分别置于正常 Krebs 溶液（2.5 mM Ca）、无钙（2 mM EGTA）Krebs 溶液中，用硝普钠（SNP）处理，或去除内皮，然后以 10 mmHg 的步长从 10 mmHg 加压至 110 mmHg，并分析直径的百分比变化，以分别测量总（主动 + 被动）、主动钙依赖性肌源性、被动和内皮依赖性张力。与 Preg 大鼠相比，RUPP 大鼠的 BP 更高，产仔数和幼仔体重更低。在正常 Krebs 溶液中，增加管腔内压力时，RUPP 大鼠动脉直径的增加幅度小于 Preg 大鼠，提示总血管张力更大。在无钙 Krebs 溶液中孵育动脉、用 SNP 处理或去除内皮可消除血管张力的差异，从总血管张力中减去这些成分后分别显示，与 Preg 大鼠相比，RUPP 大鼠存在显著的主动钙依赖性肌源性、被动和内皮依赖性张力。与 Preg 大鼠相比，RUPP 大鼠动脉的总应变-应力曲线和被动应变-应力曲线向左移动，表明子宫动脉僵硬度增加。动脉切片显示管腔/总面积减小，壁/总面积增加，免疫组织化学显示 MMP-1 和 MMP-7 染色增强，尤其是在中膜，提示与 Preg 大鼠相比，RUPP 大鼠子宫动脉存在 MMPs 介导的重塑。子宫动脉主动肌源性、被动和内皮依赖性张力增加，动脉僵硬度增加以及 MMPs 介导的重塑会进一步减少子宫血流量，加重子宫胎盘缺血、FGR 和 HTN-Preg。
