Department of Surgery, The University of Mississippi Medical Center, Jackson, Mississippi.
Department of Physiology and Biophysics, The University of Mississippi Medical Center, Jackson, Mississippi.
Am J Physiol Heart Circ Physiol. 2021 May 1;320(5):H1949-H1958. doi: 10.1152/ajpheart.00724.2019. Epub 2021 Mar 12.
The prevalence of preeclampsia and obesity have increased. Although obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in nonpregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On () , Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 µg/kg/min iv) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On , plasma leptin was elevated in Sham + Leptin and RUPP + Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP + Vehicle vs. Sham + Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared with vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling. Ours is the first study to examine the impact of hyperleptinemia on the development of placental ischemia-induced hypertension using an experimental animal model.
子痫前期和肥胖的患病率都有所增加。虽然肥胖是子痫前期的一个主要危险因素，但将这两种疾病联系起来的机制尚不清楚。循环瘦素水平与脂肪量成正比增加。这种脂肪因子的输注会在非妊娠大鼠中引起高血压，但对于高瘦素血症如何在胎盘缺血期间影响血压（子痫前期高血压病理生理学的起始事件）知之甚少。我们检验了这样一个假设，即在子宫灌注压低（RUPP）期间发生的高瘦素血症会加重胎盘缺血引起的高血压。在（），Sprague-Dawley 大鼠被植入渗透微型泵，同时输送重组大鼠瘦素（1μg/kg/min iv）或载体，以诱发胎盘缺血或假手术。在（），假手术+瘦素和 RUPP+瘦素组的血浆瘦素水平升高。瘦素输注对假手术组的平均动脉压（MAP）没有显著影响。与假手术+载体相比，RUPP+载体组的 MAP 升高。与我们的假设相反，瘦素输注减轻了胎盘缺血引起的高血压。为了研究高瘦素血症时减轻 RUPP 引起的高血压的潜在机制，乙酰胆碱诱导的内皮依赖性血管舒张在 Sham 和 RUPP 之间相似；然而，一氧化氮（NO）供体，硝普钠诱导的内皮非依赖性血管舒张在 Sham 和 RUPP 中增加。这些发现表明，在高瘦素血症存在的情况下，NO/环鸟苷酸（cGMP）信号增加。与载体组相比，假手术和 RUPP 高瘦素血症组的血浆 cGMP 升高，但血浆和血管 NO 代谢物减少。这些数据表明，在胎盘缺血期间发生的高瘦素血症通过代偿性增加 NO/cGMP 信号来减轻高血压。我们的研究是首次使用实验动物模型研究高瘦素血症对胎盘缺血引起的高血压发展的影响。
