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Intrauterine growth restriction (IUGR) affects 5-10% of pregnancies with placental hypoxia, playing a key role as a common pathophysiological pathway of different etiologies. Despite the high metabolic rate of the placenta and its "gatekeeper" role in protecting the fetus from hypoxia, the response of placental mitochondria to hypoxic stress is not well understood. This study tested the hypothesis that transient exposure to hypoxia leads to a loss of placental mitochondria and affects their function. Human villous trophoblastic (JEG-3) cells were cultured under normoxic and hypoxic conditions for 24 h. Mitochondrial content was determined by flow cytometry before and after hypoxic exposure and after 24 h of normoxic recovery. Parameters of oxidative phosphorylation were assessed using a respirometric analyzer before hypoxic exposure and after normoxic recovery. Mitochondrial content decreased significantly from 88.5% to 26.7% during hypoxic incubation. Although it had increased to 84.2% after 24 h of normoxic recovery, oxidative phosphorylation parameters were still significantly suppressed to 1/2 to 1/3 of the pre-incubation levels. The results underscore the ability of placental cells to adapt mitochondrial content to O2 supply. Despite rapid recovery under normoxia, respiratory function remains suppressed, which may result in persistent impairment of adenosine triphosphate (ATP)-dependent synthetic and transport functions.

AbstractDiabetic foot ulcer (DFU) is a severe diabetes complication characterized by impaired angiogenesis and chronic inflammation, leading to delayed wound healing. Exosomes (Exo) derived from hypoxic adipose‐derived stem cells (H‐ADSCs‐Exo) show potential as therapeutic carriers. This study investigates the role of H‐ADSCs‐Exo carrying miR‐100‐5p in DFU healing. ADSCs were isolated, characterized, and their Exo analyzed via transmission electron microscopy, nanoparticle tracking analysis, and Western blot. Transcriptome sequencing identified miR‐100‐5p as a key modulator of angiogenesis and inflammation. In vitro, H‐ADSCs‐Exo enhanced human umbilical vein endothelial cell and fibroblast proliferation, migration, and tube formation. In a rat DFU model, H‐ADSCs‐Exo administration reduced ulcer size, increased angiogenesis (VEGF/CD31 expression), and decreased inflammatory markers (TNF‐α, IL‐6). miR‐100‐5p overexpression further amplified these effects, demonstrating its critical role in Exo‐mediated healing. These findings highlight the therapeutic potential of H‐ADSCs‐Exo in DFU treatment, offering insights into cell signaling mechanisms and paving the way for miRNA‐based regenerative therapies. This study investigates the therapeutic potential of hypoxic adipose‐derived stem cell exosomes (H‐ADSCs‐Exo) carrying miR‐100‐5p in diabetic foot ulcer (DFU) healing. Findings show that H‐ADSCs‐Exo enhance angiogenesis, suppress inflammation, and accelerate wound healing in vitro and in vivo. miR‐100‐5p plays a pivotal role in these effects, offering a novel strategy for DFU treatment.

Vascular dementia is the second most common form of dementia. Yet, the mechanisms by which cerebrovascular damage progresses are insufficiently understood. Here, we create bilateral common carotid artery stenosis in mice, which effectively impairs blood flow to the brain, a major cause of the disease. Through imaging and single-cell transcriptomics of the mouse cortex, we uncover that blood vessel venous cells undergo maladaptive structural changes associated with increased Epas1 expression and activation of developmental angiogenic pathways. In a human cell model comparing arterial and venous cells, we observe that low-oxygen condition leads to sustained EPAS1 signaling specifically in venous cells. EPAS1 inhibition reduces cerebrovascular abnormalities, microglial activation, and improves markers of cerebral perfusion in vivo. In human subjects, levels of damaged endothelial cells from venous vessels are correlated with white matter injury in the brain and poorer cognitive functions. Together, these findings indicate EPAS1 as a potential therapeutic target to restore cerebrovascular integrity and mitigate neuroinflammation. How changes in brain blood vessels lead to a chronic reduction in blood flow and, consequently, to vascular dementia is poorly understood. Here, the authors show that venous endothelial dysfunction driven by EPAS1 promotes abnormal vascular remodeling and contributes to cognitive decline.