Toronto General Hospital Research Institute, University Health Network, 101 College Street, Toronto, Ontario, M5G 1L7, Canada.
Mouse Imaging Centre, The Hospital for Sick Children, 25 Orde Street, Toronto, Ontario, M5T 3H7, Canada.
Sci Rep. 2018 Apr 26;8(1):6552. doi: 10.1038/s41598-018-24680-w.
Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro-angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women.
艾滋病毒阳性孕妇在接受联合抗逆转录病毒治疗（cART）时，不良出生结局很常见，尤其是在妊娠早期开始 cART 时。其机制仍不清楚。我们使用小鼠模型证明，从妊娠第 1 天开始接触基于蛋白酶抑制剂的 cART 与胎盘中的促血管生成/促分支转变有关，这是由较低的 Flt-1 水平和较高的 Gcm-1 表达驱动的。Micro-CT 成像显示，cART 处理的胎盘中的小动脉数量增加，这与胎儿生长受限有关。延迟 cART 的起始时间，或用孕激素补充 cART 处理的小鼠，可防止促血管生成/促分支转变和相关的胎盘血管变化。与我们的小鼠发现一致，我们观察到与 HIV 阴性对照组相比，HIV 阳性 cART 暴露妇女的胎盘终末绒毛毛细血管数量增加。毛细血管数量与母体孕激素水平呈负相关。我们的研究提供了证据，表明妊娠期间 cART 暴露会影响胎盘血管形成，这反过来可能导致胎儿生长受限。我们的研究结果强调了需要更密切地研究 HIV 阳性妊娠中的胎盘，特别是对从受孕开始就暴露于 cART 的妊娠，并且表明孕激素补充可能被作为一种改善 HIV 阳性孕妇胎盘功能的可能干预措施进行研究。
