The human placenta is the nexus of maternal–fetal exchange, with its function reflected in histological features such as syncytial knots. These nuclear aggregations within the syncytiotrophoblast, historically termed Tenney–Parker changes when excessive, serve as critical markers of both placental maturation and maladaptation. This narrative review synthesizes the current understanding of their structural, ultrastructural, and molecular features, emphasizing the biological significance of the syncytial knot index as a quantitative marker of placental function. The syncytial knot index rises progressively with gestation but increases prematurely in conditions such as preeclampsia, fetal growth restriction, maternal vascular malperfusion, and chronic hypoxia, reflecting accelerated syncytiotrophoblast aging and oxidative injury. This review also highlights the mechanistic pathways – apoptosis, senescence, hypoxia-driven signaling, and disturbed trophoblast turnover – that determine knot formation. Emerging evidence on syncytiotrophoblast-derived microparticles illustrates their potential role in mediating maternal endothelial dysfunction and systemic manifestations of placental disease. Despite its diagnostic value, the syncytial knot index remains underutilized due to methodological variability; however, digital pathology, stereology, and 3D imaging now offer promising avenues for standardized assessment.
The aim of this study was to explore the historical evolution of atherosclerosis, from early understanding of the function of the heart and blood vessels to the discovery of arterial occlusive disease. This narrative review draws on historical medical texts, archaeological findings, and recent literature. It synthesizes developments in cardiovascular understanding across ancient, classical, and modern eras, with attention to changing paradigms. Evidence of atherosclerosis has been observed in mummified remains from ancient civilizations, predating any formal understanding of the cardiovascular system. In classical antiquity, the heart and vessels were often assigned symbolic or spiritual meaning, gradually giving way to empirical inquiry and anatomical study. Eventually, atherosclerosis came to be recognized as a multifactorial disease with significant clinical consequences. The understanding of atherosclerosis has evolved through centuries of speculation, anatomical discovery, and technological innovation. These perspectives provide a non-exhaustive overview of historical concepts of the cardiovascular system and atherosclerosis in particular.
Trophoblast invasion is a finely regulated physiological process that demonstrates controlled cellular migration and vascular remodeling during human pregnancy. During normal implantation, cytotrophoblasts differentiate into extravillous trophoblasts (EVTs), which enter the maternal decidua and remodel spiral arteries, converting them into low-resistance vessels required for fetal nutrition. This balance of invasion and restraint promotes appropriate vascular adaptation at the maternal–fetal interface. Aberrations in this mechanism result in a range of pathological states, from excessive but non-malignant invasion in placenta accreta spectrum (PAS) to uncontrolled, malignant invasion in choriocarcinoma. In PAS, trophoblasts can infiltrate the myometrium due to dysregulated production of matrix metalloproteinases (MMP-2 and MMP-9), integrins, and angiogenic factors (VEGF and HIF-1α). In choriocarcinoma, trophoblastic cells activate PI3K/AKT, Wnt/β-catenin, and Notch signaling, leading to hyperproliferation, immune evasion through PD-L1, and metastatic potential. Despite differences in clinical behavior, many disorders have molecular mediators that link trophoblast invasion to vascular remodeling, angiogenesis, and immunological regulation. Emerging models, including trophoblast organoids, placental explants, and placenta-on-a-chip technologies, offer enhanced platforms to study such pathways at the cellular and molecular levels. This review highlights trophoblast invasion as a model of controlled angiogenic remodeling, providing mechanistic insight into both obstetric pathology and cancer biology. It underscores how studying placental invasion can inform therapeutic strategies targeting abnormal vascular invasion across diseases.
Graphical Abstract: Abstract:Bone morphogenetic protein (BMP) signaling pathway components play a crucial role in cardiovascular homeostasis and sprouting angiogenesis. Endothelial colony-forming cells (ECFCs) are endothelial progenitor cells with a high proliferative and angiogenic capacity and therefore are valuable candidates for angiogenic therapies and vascular regeneration. Of note, a direct comparative analysis of human umbilical cord blood-derived ECFCs (CB-ECFCs) and peripheral blood-derived ECFCs (PB-ECFCs) with a focus on BMP signaling and potential tissue-dependent effects is lacking. In this study, we characterized the BMP signaling responses in ECFCs derived from the umbilical cord and peripheral blood. Analysis of SMAD1/5 phosphorylation showed that BMP2 stimulation only leads to an activation of the BMP signaling pathway in PB-ECFCs, but not in CB-ECFCs. Analysis of gene expression levels of BMP/TGF-β type I and type II receptors demonstrated an elevated expression of ALK2 in PB-ECFCs. Evaluation of sprouting angiogenesis revealed that si-RNA-mediated silencing of ALK2 in CB-ECFCs results in hypersprouting, while si-RNA-mediated silencing of ALK3 leads to hypersprouting in PB-ECFCs. To conclude, we found a differential BMP signaling pathway activation in CB-ECFCs and PB-ECFCs, which is related to vascular bed-dependent expression of ALK2.
Atherosclerosis is a progressive inflammatory disease, of which initiation and progression are potentially mediated by myeloid cells. An imbalance of oxygen supply and, therefore, hypoxic situations in the arterial wall have been hypothesized to be a major driver of development and progression of atherosclerosis. Herein, we analyze the significance of hypoxia-inducible factor (HIF) in myeloid cells in atherosclerosis. Myeloid-specific Hif1α and Hif2α knockout mice were crossed into the ApoE−/− background, and angiotensin II (AngII) infusion was performed to induce accelerated plaque formation. Myeloid Hif1α, but not Hif2α, limited the increase in heart weight after 7 days of AngII infusion, indicating a transient protective effect restricted to early phases of AngII-induced remodeling. With prolonged treatment (4 weeks), these differences were lost, suggesting a protective role for myeloid HIF-1α only in early hypertension-induced cardiac hypertrophy. Macrophages of aged mice (12 months old) showed decreased expression of Hif1α and Hif2α, which did not yield overt differences in classical/alternative polarization markers. Nevertheless, aged ApoE−/− mice with macrophage-specific Hif1α knockout had a higher body weight and developed more aortic plaques compared to wild-type littermates. These observations suggest that activation of Hif1α in macrophages may be protective for plaque formation under chronic hyperlipidemic conditions. Supporting this, a reanalysis of single-cell RNA-sequencing data from human atherosclerotic and normal vessel wall specimens shows that HIF target gene expression is elevated in anti-inflammatory macrophage subsets along pseudotime trajectories. This association suggests that macrophage HIF1α activity may contribute to reparative or stabilizing responses during plaque progression.
