Drobnjak Tijana, Jónsdóttir Anna Margrét, Helgadóttir Helga, Runólfsdóttir Margrét Soffía, Meiri Hamutal, Sammar Marei, Osol George, Mandalà Maurizio, Huppertz Berthold, Gizurarson Sveinbjörn
Faculty of Pharmaceutical Sciences, School of Health Science, University of Iceland, Reykjavik, Iceland,
Department of Pathology, University Hospital Iceland, Reykjavik, Iceland.
Int J Womens Health. 2019 Mar 27;11:213-222. doi: 10.2147/IJWH.S188303. eCollection 2019.
Reduced concentrations of placental protein 13 (PP13) during the first trimester of human pregnancy are associated with elevated risk for the subsequent development of preeclampsia, which is one of the deadliest obstetrical complications of pregnancy. Previous studies by our group have shown that PP13 lowers blood pressure in pregnant rats, increases the size and weight of pups and placentas, and induces vasodilation of resistance arteries through endothelial signaling pathways involving endothelial nitric oxid synthase and prostaglandin.
In the present study, the effect of PP13 was investigated in nonpregnant female Sprague Dawley rats (n=27). Osmotic pumps were surgically implanted subcutaneously that released a constant dose of PP13 or saline over 7 days. Most animals were sacrificed 6 days after the end of PP13 release (on day 13), while some were sacrificed immediately at the end of day 7 (the last PP13 release day), to compare the short- and long-term impact of PP13 on vessels' growth and size.
The uterine vessels were significantly expanded in the group exposed to recombinant PP13 (rPP13) compared to the control (saline) group. Both veins and arteries were significantly expanded by rPP13 with a more pronounced effect after 13 days compared to the corresponding vessels after 7 days. Furthermore, the long-term effect of treatment by rPP13 was more pronounced in the veins compared to the corresponding arteries. The effect of a PP13 variant with a histidine-tag (His-PP13) remained the same between 7 and 13 days.
In conclusion, PP13 might play a key role in the expansive remodeling of the uterine vessels, reflecting what would happen if the rat was pregnant, preparing the uterine vascu-lature for the increase in uteroplacental blood flow, which is necessary for normal pregnancy. We suggest that PP13 could act by NO signaling pathways, a hypothesis that requires future study.
在人类妊娠的头三个月，胎盘蛋白13（PP13）浓度降低与子痫前期后续发生风险升高有关，子痫前期是妊娠最致命的产科并发症之一。我们小组之前的研究表明，PP13可降低妊娠大鼠的血压，增加幼崽和胎盘的大小及重量，并通过涉及内皮型一氧化氮合酶和前列腺素的内皮信号通路诱导阻力动脉血管舒张。
在本研究中，对未怀孕的雌性Sprague Dawley大鼠（n = 27）进行了PP13作用的研究。通过手术将渗透泵皮下植入，使其在7天内释放恒定剂量的PP13或生理盐水。大多数动物在PP13释放结束后6天（第13天）处死，而一些动物在第7天结束时（最后一次PP13释放日）立即处死，以比较PP13对血管生长和大小的短期和长期影响。
与对照组（生理盐水组）相比，暴露于重组PP13（rPP13）的组子宫血管明显扩张。rPP13使静脉和动脉均显著扩张，与7天后的相应血管相比，13天后的效果更明显。此外，与相应动脉相比，rPP13治疗的长期效果在静脉中更显著。带有组氨酸标签的PP13变体（His-PP13）在7至13天之间的效果保持不变。
总之，PP13可能在子宫血管的扩张性重塑中起关键作用，反映了大鼠怀孕时会发生的情况，为子宫胎盘血流增加准备子宫血管系统，这是正常妊娠所必需的。我们认为PP13可能通过NO信号通路起作用，这一假设需要未来进一步研究。
