Department of Surgery, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi.
Aggamin Biologics, New York, New York, USA.
J Hypertens. 2020 Nov;38(11):2295-2304. doi: 10.1097/HJH.0000000000002528.
Although epidemiological studies have shown that obesity is associated with increased incidence of hypertension during pregnancy, the mechanisms linking these two comorbidities are not as well studied. Previous investigations detected lower levels of the anti-hypertensive and pregnancy-related factor, placental growth factor (PlGF), in obese hypertensive pregnancies. Therefore, we examined whether obese hypertensive pregnant rats have reduced PlGF and whether increasing its levels by administering recombinant human (rh)PlGF reduces their blood pressure.
We utilized a genetic model of obesity characterized to be heavier, hypertensive and fertile, namely rats having heterozygous deficiency of the melanocortin-4 receptor (MC4R-def).
MC4R-def obese rats had lower circulating levels of PlGF than wild-type lean controls at gestational day 19. Also, assessment of the PlGF receptor, Flt-1, in the vasculature showed that its levels were reduced in aorta and kidney glomeruli but increased in small mesenteric arteries. Chronic intraperitoneal administration of rhPlGF from gestational day 13-19 significantly increased circulating PlGF levels in both obese and lean rats, but reduced blood pressure only in the obese pregnant group. The rhPlGF treatment did not alter maternal body and fat masses or circulating levels of the adipokines, leptin and adiponectin. In addition, this treatment did not impact average foetal weights but increased placental weights regardless of obese or lean pregnancy.
PlGF is reduced in MC4R-def obese hypertensive pregnant rats, which is similar to findings in obese hypertensive pregnant women, while increasing its levels with exogenous rhPlGF reduces their blood pressure.
尽管流行病学研究表明肥胖与妊娠期间高血压的发生率增加有关，但将这两种合并症联系起来的机制尚未得到充分研究。先前的研究发现，肥胖合并高血压妊娠中的抗高血压和妊娠相关因子胎盘生长因子（PlGF）水平较低。因此，我们检查了肥胖合并高血压妊娠大鼠的 PlGF 是否减少，以及通过给予重组人（rh）PlGF 增加其水平是否降低其血压。
我们利用了一种以肥胖为特征的遗传模型，即杂合子黑素皮质素 4 受体（MC4R-def）缺乏的大鼠，该模型表现为体重增加、高血压和生育力正常。
MC4R-def 肥胖大鼠在妊娠第 19 天的循环 PlGF 水平低于野生型瘦对照大鼠。此外，对血管中的 PlGF 受体 Flt-1 的评估表明，其在主动脉和肾小球中的水平降低，但在小肠系膜动脉中升高。从妊娠第 13-19 天开始，慢性腹腔内给予 rhPlGF 可显著增加肥胖和瘦大鼠的循环 PlGF 水平，但仅降低肥胖妊娠组的血压。rhPlGF 治疗并未改变母体体重和脂肪量或循环中的脂肪因子瘦素和脂联素水平。此外，这种治疗并未影响平均胎儿体重，但增加了胎盘重量，无论肥胖或瘦的怀孕情况如何。
MC4R-def 肥胖合并高血压妊娠大鼠的 PlGF 减少，这与肥胖合并高血压孕妇的发现相似，而通过外源性 rhPlGF 增加其水平可降低其血压。
