Vascular biology (Bristol, England)最新文献

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 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 the 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 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.

The 2025 Australasian Summit on Vascular Biology and Microcirculation, jointly hosted by the Australian Vascular Biology Society (AVBS) and the Australian and New Zealand Microcirculation Society (ANZMS), convened in Queenstown, New Zealand, bringing together researchers, clinicians, and trainees across diverse disciplines. The meeting featured plenary lectures, award finalist presentations, and thematic sessions spanning vascular pathology and therapeutic discovery, extracellular matrix dynamics, (lymph) angiogenesis, inflammation, and cerebrovascular biology. Early career researchers and PhD students showcased cutting-edge work, underscoring the vibrancy of the next generation of vascular scientists. A dedicated science communication workshop further enriched the program, promoting effective dissemination and impact of vascular biology research. This report summarises the key scientific advances presented, emerging therapeutic targets, and collaborative opportunities that are shaping the future of vascular biology in Australasia and beyond.

Blood flow within the vasculature is a critical determinant of endothelial cell (EC) identity and functionality, yet the intricate interplay of various hemodynamic forces and their collective impact on endothelial and vascular responses is not fully understood. Specifically, the role of hydrostatic pressure in the EC flow response is understudied, despite its known significance in vascular development and disease. To address this gap, we developed in vitro models to investigate how pressure influences EC responses to flow. Our study demonstrates that elevated pressure conditions significantly modify shear-induced flow alignment and increase EC density. Bulk and single-cell RNA sequencing analyses revealed that, while shear stress remains the primary driver of flow-induced transcriptional changes, pressure modulates shear-induced signaling in a dose-dependent manner. These pressure-responsive transcriptional signatures identified in human ECs were conserved during the onset of circulation in early mouse embryonic vascular development, where pressure was notably associated with transcriptional programs essential to arterial and hemogenic EC fates. Our findings suggest that pressure plays a synergistic role with shear stress on ECs and emphasize the need for an integrative approach to EC mechanotransduction, one that encompasses the effects induced by pressure alongside other hemodynamic forces.

Vascular aging is a multifactorial process characterized by structural and functional changes that compromise endothelial homeostasis and increase the risk of cardiovascular disease. Among the factors involved in this process, methylarginines, such as asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and NG-monomethyl-L-arginine (L-NMMA), stand out. These negatively modulate nitric oxide (NO) bioavailability, compromising endothelial function. This systematic review aimed to investigate the relationship between vascular aging and methylarginine levels, considering their influence on endothelial dysfunction and its impact on human health. The systematic search was conducted in scientific databases, resulting in the inclusion of four studies: three observational studies in humans and one experimental study in vitro. The findings demonstrated that elevated levels of ADMA, SDMA, and L-NMMA are associated with the progression of endothelial dysfunction, increased cardiovascular risk, and cognitive impairment in the elderly. The in vitro study reinforced this evidence by demonstrating that increasing concentrations of ADMA accelerate endothelial cell senescence, reduce telomerase activity, and decrease NO production. Interpretation of the results should consider the methodological limitations of the included studies, but the findings reinforce the role of methylarginines as potential biomarkers of vascular aging and highlight the need for further investigations exploring therapeutic strategies to minimize their deleterious effects.

The placenta is a highly vascularised organ that depends on tightly regulated angiolymphatic networks to sustain normal fetal growth and maternal adaptation to pregnancy. Disruption of these pathways contributes to major obstetric complications, including preeclampsia, fetal growth restriction, gestational diabetes, and stillbirth. In recent years, advances in molecular pathology and high-throughput technologies have identified a spectrum of angiogenic, lymphangiogenic, and endothelial biomarkers that provide mechanistic insights and hold translational promise. Among these, vascular endothelial growth factors (VEGF-A, VEGF-C, VEGF-D), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), angiopoietins, podoplanin, and lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1) have emerged as key regulators. Differential expression of these markers in placental tissue, maternal circulation, and extracellular vesicles has been correlated with disease severity, placental morphology, and adverse neonatal outcomes. Despite growing evidence, clinical application is limited by methodological heterogeneity, gestational age-specific variability, and incomplete understanding of lymphatic involvement in placental physiology. This review synthesises current knowledge on angiolymphatic biomarkers in the placenta, highlighting their role in vascular development, disease pathogenesis, and potential as diagnostic and prognostic tools. Future research integrating molecular assays, imaging modalities, and systems biology approaches is essential to standardise biomarker panels and translate them into clinically meaningful strategies for maternal-fetal medicine.

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Abstract: Endothelial cells regulate vascular tone by releasing nitric oxide (NO) and prostacyclin (PGI2), as well as by initiating hyperpolarization of vascular smooth muscle cells through K+ channels and myoendothelial coupling. This review highlights the therapeutic potential of targeting endothelium-dependent hyperpolarization (EDH) to address unmet needs in microvascular disorders such as cerebral small vessel disease, an important cause of stroke and dementia, and preeclampsia, a major pregnancy complication associated with maternal and fetal morbidity. Oxidative stress, connexin dysfunction, and impaired K+ channel signaling disrupt electrical coupling between endothelium and smooth muscle cells, leading to loss of vascular homeostasis. Building on this mechanistic convergence, we propose a multimodal therapeutic strategy to restore EDH in concert with the NO and PGI2 pathways. Within this framework, human tissue kallikrein-1 (KLK1) exemplifies an integrated therapeutic approach by simultaneously engaging multiple endothelial vasodilator mechanisms. Through bradykinin B2 receptor signaling, KLK1 enhances NO and PGI2 production while also promoting EDH via K+ channel activation. Its recombinant form, rinvecalinase alfa (DM199), has demonstrated consistent benefit in early-phase clinical trials, supporting its potential to restore endothelial balance. By reactivating these complementary vasodilatory pathways, DM199 improves microvascular perfusion and endothelial resilience, positioning it as a prototype multimodal therapy for microvascular diseases.

Key message: Restoring endothelium-derived hyperpolarization alongside NO and prostacyclin signaling represents a promising multimodal approach to treat endothelial dysfunction and microvascular disorders.

Activating transcription factor 6 (ATF6) is an unfolded protein response sensor with a significant role in endothelial integrity and barrier function. This study investigates the effects of Ceapin-A7, which is an ATF6 inhibitor, in mediating the protective effects of pasireotide (PAS) in the endothelium. Ceapin-A7 suppressed PAS-induced glucose-regulated protein 94 (GRP94) augmentation, cofilin deactivation, and MLC2 dephosphorylation. Furthermore, ATF6 inhibition counteracted the anti-oxidative and anti-inflammatory effects of PAS in human and bovine lung endothelial cells, as evidenced by increased ROS generation and suppression of pSTAT1, pSTAT3, pERK1/2, and pP38. Our study adds information on the protective actions of pasireotide in endothelial cells and supports ongoing efforts to enrich our knowledge of the pathophysiology of sepsis and lung injury.

Therapeutic neovascularization is a promising therapy option for patients with peripheral arterial disease. We followed in time the gene expression after induction of hind limb ischemia in mice with different patterns of blood flow restoration and identified lipocalin 2 (LCN2) as a strongly upregulated factor whose role in neovascularization deserves further investigation. In this study, we investigated the role of LCN2 in angiogenesis using the hind limb ischemia (HLI) model, ex vivo angiogenic aortic ring assay, and by assessing the pre-existing collaterals in the pial circulation in both Lcn2 -/- mice and wild-type (WT) mice. This demonstrated an upregulated mRNA expression of Lcn2 after HLI and reduced post-ischemic angiogenesis in Lcn2 -/- compared to WT mice. In the aortic ring assay, angiogenic sprouting was decreased in Lcn2 -/- compared to WT mice. The blood flow recovery and arteriogenesis after HLI and preexisting collateral density in the pial circulation were similar in Lcn2 -/- and WT mice. In vitro, siRNA-mediated LCN2 knockdown impaired HMVEC migration and tube formation. These results show that LCN2 is a potential pro-angiogenic factor and that LCN2 downregulation has a negative effect on angiogenesis in vivo and in vitro.

To investigate the effects of the dopamine D4 receptor agonist A-412997 and the D4 antagonist sonepiprazole in human isolated umbilical artery (HUA) and vein (HUV) and the expression of the D4 receptor by immunohistochemistry in these vessels. A segment of the umbilical cord (10-20 cm) from the insertion point in the placenta and 5 cm from the umbilicus was removed by the obstetrician and placed in a container with Krebs-Henseleit solution (KHS). The Wharton's jelly was removed, and HUA and HUV rings (3 mm) were suspended in 10 mL organ baths containing oxygenated (95% O2:5% CO2) and heated (37 °C) KHS. For immunohistochemistry, the vessels were fixed in 10% formalin, embedded in paraffin wax and sectioned (4 µm). A-412997 did not induce contractions in the HUA rings. In HUA pre-contracted rings, A-412997 induced concentration-dependent relaxations, which were reduced when the HUA rings were pre-incubated with L-NAME. A-412997 caused concentration-dependent contractions of HUV rings, which were potentiated by pre-treatment with L-NAME and reduced by pre-incubation with 6-nitrodopamine. In HUV pre-contracted rings, A-412997 failed to induce relaxations. Sonepiprazole antagonized A-412997-induced contractions in HUV rings and provoked concentration-dependent relaxations in pre-contracted HUA and HUV rings. Dopamine D4 receptor was positive in both HUA and HUV, especially in the endothelium, and detected only in HUV smooth muscle cells. Activation of HUA D4 receptor is associated with relaxation, whereas in HUV, it leads to contraction. Differential expression of D4 receptors may modulate umbilical-placental blood flow.