Vargas Vladimir E, Landeros Rosalina Villalon, Lopez Gladys E, Zheng Jing, Magness Ronald R
Department of Ob/Gyn, University of Wisconsin, Madison, Wisconsin, USA.
Department of Ob/Gyn, Perinatal Research Vascular Center, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
Biol Reprod. 2017 Apr 1;96(4):866-876. doi: 10.1093/biolre/iox008.
Leptin regulates body weight, reproductive functions, blood pressure, endothelial function, and fetoplacental angiogenesis. Compared to the luteal phase, the follicular phase and pregnancy are physiological states of elevated estrogen, angiogenesis, and uterine blood flow (UBF). Little is known concerning regulation of uterine artery (UA) angiogenesis by leptin and its receptors. We hypothesized that (1) ex vivo expression of leptin receptors (LEPR) in UA endothelium (UAendo) and UA vascular smooth muscle (UAvsm) is elevated in pregnant versus nonpregnant (Luteal and Follicular) sheep; (2) in vitro leptin treatments differentially modulate mitogenesis in uterine artery endothelial cells from pregnant (P-UAECs) more than in nonpregnant (NP-UAECs) ewes; and (3) LEPR are upregulated in P-UAECs versus NP-UAECs in association with leptin activation of phospho-STAT3 signaling. Local UA adaptations were evaluated using a unilateral pregnant sheep model where prebreeding uterine horn isolation (nongravid) restricted gravidity to one horn. Immunolocalization revealed LEPR in UAendo and UAvsm from pregnant and nonpregnant sheep. Contrary to our hypothesis, western analysis revealed that follicular UAendo and UAvsm LEPR were greater than luteal, nongravid, gravid, and control pregnant. Compared to pregnant groups, LEPR were elevated in renal artery endothelium of follicular and luteal sheep. Leptin treatment significantly increased mitogenesis in follicular phase NP-UAECs and P-UAECs, but not luteal phase NP-UAECs. Although UAEC expression of LEPR was similar between groups, leptin treatment only activated phospho-STAT3 in follicular NP-UAECs and P-UAECs. Thus, leptin may play an angiogenic role particularly in preparation for the increased UBF during the periovulatory period and subsequently to meet the demands of the growing fetus.
瘦素调节体重、生殖功能、血压、内皮功能以及胎儿-胎盘血管生成。与黄体期相比，卵泡期和孕期是雌激素水平升高、血管生成增加以及子宫血流量（UBF）增加的生理状态。关于瘦素及其受体对子宫动脉（UA）血管生成的调节作用，人们了解甚少。我们推测：（1）与未怀孕（黄体期和卵泡期）的绵羊相比，怀孕绵羊的UA内皮（UAendo）和UA血管平滑肌（UAvsm）中瘦素受体（LEPR）的体外表达升高；（2）体外瘦素处理对怀孕母羊（P-UAECs）子宫动脉内皮细胞有丝分裂的调节作用比对未怀孕母羊（NP-UAECs）更强；（3）与磷酸化STAT3信号通路的瘦素激活相关，P-UAECs中的LEPR比NP-UAECs上调。使用单侧怀孕绵羊模型评估UA局部适应性，其中配种前子宫角隔离（未受孕）将妊娠限制在一个子宫角。免疫定位显示怀孕和未怀孕绵羊的UAendo和UAvsm中有LEPR。与我们的假设相反，蛋白质印迹分析显示卵泡期UAendo和UAvsm的LEPR大于黄体期、未受孕、受孕和对照怀孕组。与怀孕组相比，卵泡期和黄体期绵羊肾动脉内皮中的LEPR升高。瘦素处理显著增加卵泡期NP-UAECs和P-UAECs的有丝分裂，但不增加黄体期NP-UAECs的有丝分裂。尽管各组之间UAEC中LEPR的表达相似，但瘦素处理仅激活卵泡期NP-UAECs和P-UAECs中的磷酸化STAT3。因此，瘦素可能发挥血管生成作用，特别是在排卵前期为增加的UBF做准备，并随后满足不断生长胎儿的需求。
