Maternal and fetal mitochondrial gene dysregulation in hypertensive disorders of pregnancy.

Mitochondrial dysfunction has been implicated in pregnancy-induced hypertension (PIH). The role of mitochondrial gene dysregulation in PIH, and consequences for maternal-fetal interactions, remain elusive. Here, we investigated mitochondrial gene expression and dysregulation in maternal and placental tissues from pregnancies with and without PIH; further, we measured circulating mitochondrial DNA (mtDNA) mutational load, an index of mtDNA integrity. Differential gene expression analysis followed by Time Course Gene Set Analysis (TcGSA) was conducted on publicly available high throughput sequencing transcriptomic data sets. Mutational load analysis was carried out on peripheral mononuclear blood cells from healthy pregnant individuals and individuals with preeclampsia. Thirty mitochondrial differentially expressed genes (mtDEGs) were detected in the maternal cell-free circulating transcriptome, whereas nine were detected in placental transcriptome from pregnancies with PIH. In PIH pregnancies, maternal mitochondrial dysregulation was associated with pathways involved in inflammation, cell death/survival, and placental development, whereas fetal mitochondrial dysregulation was associated with increased production of extracellular vesicles (EVs) at term. Mothers with preeclampsia did not exhibit a significantly different degree of mtDNA mutational load. Our findings support the involvement of maternal mitochondrial dysregulation in the pathophysiology of PIH and suggest that mitochondria may mediate maternal-fetal interactions during healthy pregnancy.NEW & NOTEWORTHY This study identifies aberrant maternal and fetal expression of mitochondrial genes in pregnancies with gestational hypertension and preeclampsia. Mitochondrial gene dysregulation may be a common etiological factor contributing to the development of de novo hypertension in pregnancy-associated hypertensive disorders.

HIV-1 infection renders brain vascular pericytes susceptible to the extracellular glutamate.

Reduced pericytes' coverage of endothelium in the brain is one of the structural changes leading to breach of the blood-brain barrier during HIV infection. We previously showed in central memory T (TCM) cells that HIV latency increases cellular susceptibility to DNA damage. In this study, we investigated susceptibility of primary brain pericytes infected with HIV-1 to DNA damage in response to glutamate and TNF-α, both known to induce neuronal death during chronic inflammatory conditions. To infect pericytes, we used a single-cycle HIV-1 pseudotyped with VSV-G envelope glycoprotein and maintained the cultures until latency was established. Our data indicate that pericytes silence HIV-1 expression at similar rate compared to primary TCM cells. TNF-α and IL-1ß caused partial reactivation of the virus suggesting that progression of disease and neuroinflammation might facilitate virus reactivation from latency. Significant increases in the level of γH2AX, which reflect DNA damage, were observed in infected cultures exposed to TNF-α and glutamate at day 2 post-infection. Glutamate, an excitatory neurologic stimuli, also caused increases in the γH2AX level in latently infected pericytes, whereas PARP and DNA-PK inhibitors caused reductions in cell population suggesting that HIV-1 latency affects repairs of single- and double-strand DNA breaks. For comparison, we also analyzed latently infected astrocytes and determined that DNA damage response in astrocytes is less affected by HIV-1. In conclusion, our results indicate that productive infection and HIV-1 latency in pericytes interfere with DNA damage response, rendering them vulnerable to the agents that are characteristic of chronic neuroinflammatory disease conditions.