Placental Microvasculature in Pregnancies Complicated by HIV

项目摘要 HIV阳性妊娠的不同结局，如胎儿生长受限（FGR）， 这是可以理解的，但归因于子宫胎盘功能不全。FGR是一种严重的不良结局， 与HIV暴露婴儿的持续发病率相关。迫切需要进一步的研究， 了解胎盘病理生理学，以预测，诊断，监测，并可能 预防FGR。我们之前的研究表明生殖系统微血管氧化应激增加 年龄妇女艾滋病毒感染者（WLHIV），并暗示可能的胎盘病理生理学。臀肌活检 无明显心血管危险因素的绝经前WLHIV显示严重的内皮功能障碍， 减少一氧化氮。这些在非妊娠WLHIV中的发现可能代表了未来WLHIV的早期标志物。 心血管疾病的发病率和潜在的全身微血管功能障碍的问题，包括在 胎盘虽然臀肌组织的这些发现不能直接外推到胎盘 微血管，我们假设HIV感染或ART对微血管有潜在的全身性影响， 微血管病理生理学，同样影响胎盘，对胎儿有不利影响 增长关于人类胎盘微血管的文献有限，特别是对胎盘生长的研究 限制，产生了相互矛盾的结果，主要是由于方法的不一致。 为了进一步探索这一假设，我们提出了一项试点研究，以复制臀肌中使用的方法。 组织中的胎盘组织，并表征胎盘微血管一氧化氮（NO），反应性 妊娠合并HIV的氧自由基（ROS）、收缩力和内皮功能障碍， 增长限制。解决艾滋病毒相关的合并症和并发症，特别是 心血管疾病，是NIH艾滋病研究办公室的优先事项， 与妊娠合并HIV相关的不良结局的潜在病理生理学 对WLHIV及其妊娠具有至关重要的意义。具体而言，我们的目标是：（1） 确定测量微血管收缩性和内皮功能的最佳方法， 并改进以前用于测量胎盘的实验室方法 臀肌组织中的参数; 2）进行微血管NO差异的定量评价， 12例妊娠合并HIV的胎盘中的ROS、收缩力和内皮功能障碍 无FGR的孕妇和12例HIV阴性匹配的有或无FGR的孕妇的胎盘。 这项试点研究是更好地理解、诊断和管理 胎盘病理生理学与妊娠期不良胎儿和新生儿结局相关 艾滋病并发症

PROJECT SUMMARY Disparate outcomes in HIV positive pregnancies, such as fetal growth restriction (FGR), are etiologically poorly understood, but are attributed to uteroplacental insufficiency. FGR is a serious adverse outcome with associated lasting morbidity for the HIV exposed infant. Further research is desperately needed to better understand the placental pathophysiology in order to predict, diagnose, monitor, and potentially prevent FGR. Our previous research demonstrated increased microvascular oxidative stress in reproductive age women living with HIV (WLHIV) and alludes to a possible placental pathophysiology. Gluteal biopsies in premenopausal WLHIV without overt cardiovascular risk factors revealed severe endothelial dysfunction and reduced nitric oxide. These finding in non-pregnant WLHIV may represent early markers of future cardiovascular morbidity and beg the question of possible systemic microvascular dysfunction, including in the placenta. Although these findings in gluteal tissue cannot be directly extrapolated to placental microvasculature, we hypothesize that there is of potential systemic effect of HIV infection or ART on microvascular pathophysiology, similarly affecting the placenta, with a detrimental effect on fetal growth. The limited literature on human placental microvessels, particularly studies of placentas with growth restriction, yielded conflicting results largely attributable to methodological inconsistencies. To further explore this hypothesis, we are proposing a pilot study to replicate the methodology used in gluteal tissue in placental tissue and to characterize differences in placental microvascular nitric oxide (NO), reactive oxygen species (ROS), contractility, and endothelial dysfunction in pregnancies complicated by HIV and growth restriction. Addressing HIV-associated comorbidities and complications, specifically cardiovascular, are stated priorities of the NIH Office of AIDS Research and better understanding the underlying pathophysiology of the adverse outcomes related to pregnancies complicated by HIV have critically important implications for WLHIV and their pregnancies. Specifically our aims are 1) To determine the best methods of measuring contractility and endothelial function of microvessels in the human placenta and to adapt laboratory methodologies previously employed to measure the same parameters in gluteal tissue; 2) To undertake a quantitative evaluation of differences in microvascular NO, ROS, contractility, and endothelial dysfunction in 12 placentas of pregnancies complicated by HIV with and without FGR and 12 placentas of pregnancies in HIV-negative matched controls with and without FGR. This pilot research is the crucial next step to better understanding, diagnosing and managing the placental pathophysiology associated with adverse fetal and neonatal outcomes in pregnancies complicated by HIV.