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.
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.
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.
Graphical Abstract: 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.
Blood flow restriction exercise (BFRE) is a therapeutic approach traditionally used to facilitate muscular strength and hypertrophy. Emerging evidence has identified its benefits on other systems and metabolic processes. The emphasis of this study was to examine potential impact of BFRE on serum levels of tissue plasminogen activator (tPA). Eighteen healthy adults (nine males, nine females; mean age: 34.44 ± 9.97) were randomized into groups to perform cycling either with or without blood flow restriction (BFR). Blood samples were collected before and after exercise to analyze serum concentrations of tPA. Significance in tPA between exercise groups did not reach significance but did show a large effect size (0.14) in favor of the BFR group. The trend suggests that this study was underpowered to reach significance. Further research should continue examining the impact of BFRE on serum levels of tPA. This methodology could be adapted to other populations to increase generalizability of results.
Donor liver preservation methods and solutions have evolved over the last years. Liver sinusoidal endothelial cell (LSEC) barrier function and integrity during preservation are crucial for outcomes of liver transplantation. Therefore, the present study aimed to determine optimal preservation of LSEC barrier function and integrity using different preservation solutions. Human umbilical vein endothelial cells (HUVECs) and LSECs were incubated in either University of Wisconsin machine perfusion solution (UW-MPS), histidine-tryptophan-ketoglutarate, or endothelial cell growth medium 2 (EGM2) (as a gold standard for cell culturing). Endothelial integrity was assessed by measurement of cellular morphology and expression of membrane proteins: PECAM-1, ICAM-1 and Fc-gamma receptor CD32b (FcΥRCD32b). Endothelial barrier function was measured by electric cell-substrate impedance sensing. Cellular response to inflammatory stimuli with tumor necrosis factor-alpha (TNF-α) was tested by studying trans-endothelial migration (TEM) under flow conditions. Differences in these parameters were analyzed between the different preservation solutions. PECAM-1 expression was high for all preservation solutions in HUVECs and LSECs. ICAM-1 expression was increased in both LSECs and HUVECs in all preservation solutions plus TNF-α. UW reduced PECAM-1 expression, whereas EGM2 medium promoted barrier function in LSECs and HUVECs, and monolayer recovery after wounding was best achieved in cells incubated in EGM2. LSECs and HUVECs incubated with EGM2 plus TNF-α both supported neutrophil adhesion and TEM, but much less to none when incubated in UW plus TNF-α. Overall, EGM2 showed the best results in preserving endothelial barrier function for both HUVECs and LSECs.
Although mice are used extensively to study atherosclerosis of different vascular beds, limited data are published on the occurrence of intracranial atherosclerosis. Since intracranial atherosclerosis is a common cause of stroke and is associated with dementia, a relevant animal model is needed to study these diseases. We examined the presence of intracranial atherosclerosis in different atherogenic mouse strains and studied differences in vessel wall characteristics in mouse and human tissue in search of possible explanations for the differing atherosclerotic susceptibility between extracranial and intracranial vessels. The presence of atherosclerotic plaques was systematically examined from the distal common carotids to the circle of Willis in three atherogenic mouse models. Extra- and intracranial vessel characteristics were studied by immunohistochemistry. All three strains developed atherosclerotic lesions in the common carotids, while no lesions were found intracranially. This coincided with altered vessel morphology. Compared to extracranial sections, intracranially the number of elastic layers decreased, tight junction markers increased, and antioxidant enzyme heme oxygenase (HO)-1 increased. Higher HO-1 expression was also shown in human intracranial arteries. Human brain endothelial cell stimulation with oxidized LDL induced endogenous protective antioxidant HO-1 levels through NRF2 translocation. Intracranial atherosclerosis was absent in three atherogenic mouse models. Intracranial vessel segments showed an increased presence of junction markers in mice and increased HO-1 in both mice and human tissue. We suggest that differences in brain vessel structure and induced antioxidant levels in the brain endothelium found in mouse and human tissue may contribute to the decreased atherosclerosis susceptibility of intracranial arteries.
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.
Insulin resistance underpins the progression of type 2 diabetes mellitus and leads to a collection of risk factors for the development of atherosclerosis. Whether or not insulin resistance at a whole-body level per se leads to accelerated atherosclerosis is unclear. To answer this question, we generated atherosclerosis-prone mice with whole-body insulin resistance secondary to haploinsufficiency of the insulin receptor (IR+/−) deficient in ApoE−/− (IR+/−/ApoE−/−). IR+/−/ ApoE−/− and ApoE−/− littermates had similar weight, lipids, and glucose tolerance at baseline. After 12 weeks of Western high-cholesterol diet, IR+/−/ApoE−/− had significantly more atherosclerosis in the thoracoabdominal aorta and at the level of the aortic sinus than ApoE−/− littermates. Excess Nox2 NADPH oxidase (Nox2) derived superoxide has been suggested to underpin diabetes-related atherosclerosis. In IR+/−/ApoE−/− we examined the effect of inhibiting Nox2 using genetic or pharmacological approaches on the development of atherosclerosis. To genetically delete Nox2, we generated IR+/−/ApoE−/−/Nox2−/y and to inhibit Nox2 pharmacologically, we treated IR+/−/ApoE−/− with the peptide Nox2 inhibitor gp91dstat. IR+/−/ApoE−/−/Nox2−/y had significant disruption of the aortic wall with increased thoracoabdominal atherosclerosis when compared to IR+/−/ApoE−/−/Nox2+/y littermates. Inhibition of Nox2 using gp91dstat reduced atherosclerosis in the thoracoabdominal aorta of IR+/−/ApoE−/−. Whole-body insulin resistance accelerates the development of atherosclerosis. Genetic inhibition of Nox2 leads to disruption of the aortic wall in IR+/−/ApoE−/− mice with accelerated atherosclerosis, whereas pharmacological Nox2 inhibition reduces atherosclerosis in IR+/−/ApoE−/− without disruption of the arterial wall.
Chronic limb-threatening ischemia (CLTI) is a critical end-stage disease that leads to high amputation rates. Over the past few decades, therapeutic angiogenesis has attracted a lot of attention as a means to reduce the necessity for amputations. Especially gene- and cell therapy are regarded to as possible treatment modalities to restore the hampered blood flow. So far, early-phase clinical trials often fail to prove a significant clinical improvement in mortality, amputation rate, and ulcer healing but still conclude that therapeutic angiogenesis might be promising as therapy. The subsequent phase III clinical trials based on these indecisive early trials fail consistently to demonstrate clinical benefits leaving the promising early results unvalidated. In this review we will illustrate that designing good trials for CLTI patients is challenging, not in the last place since patients are often not eligible due to strict inclusion criteria. Moreover, in this review, we advocate that clinical trials should be conducted with a low risk of bias and that it is of utmost importance to publish results, regardless of the outcome. It is definitely very concerning that many studies of a lower quality (due to small group size or high chance for bias) reporting positive outcomes are published while good quality trials (often with larger group sizes) are stopped prematurely due to lack of effects and remain unpublished. This keeps the 'promising but not yet proven' image of these therapeutic neovascularization studies alive, with still new groups starting similar trials.
The impact of α-tocopherol on atherosclerosis is unclear and controversial. While some studies suggest potential benefits, such as antioxidant properties that may reduce oxidative stress, other studies indicate no significant preventive effects. The intricate interplay of various factors, including dosage, individual differences, and study methodologies, contributes to the ongoing uncertainty surrounding α-tocopherol’s role in atherosclerosis. Further research is needed to clarify its impact and establish clearer guidelines. Therefore, we aimed to evaluate the impact of α-tocopherol on atherogenesis in ApoE−/− fibrillin (Fbn)1C1039G/+ mice, which is a unique mouse model of advanced atherosclerosis with typical features, such as large necrotic cores, high levels of inflammation, and intraplaque neovascularization, that resemble the unstable phenotype of human plaques. ApoE−/− Fbn1C1039G+/− mice were fed a western-type diet (WD) supplemented with a high dose of α-tocopherol (500 mg/kg diet), while control mice were fed a WD containing a low dose of α-tocopherol (50 mg/kg diet). The high dose of α-tocopherol reduced plaque thickness and necrotic core area in the right common carotid artery (RCCA) after 24 weeks WD. Moreover, α-tocopherol decreased plaque formation and intraplaque neovascularization in the RCCA. In addition to its antiatherogenic effect, chronic supplementation of α-tocopherol improved cardiac function in ApoE−/− Fbn1C1039G/+ mice. However, chronic supplementation of α-tocopherol did not decrease lipid peroxidation. On the contrary, α-tocopherol acted as a prooxidant by increasing plasma levels of oxidized LDL and plaque malondialdehyde, an end product of lipid peroxidation. Our data indicate that α-tocopherol inhibits atherogenesis and improves cardiac function independent of its antioxidant properties.
Graphical abstract Abstract Renin–angiotensin system plays a critical role in blood pressure control, and the abnormal activation of the AT1 receptor contributes to the development of renovascular hypertension. This study aimed to evaluate the underlying cellular signaling for AT1 receptor activation by Ang II and to compare this mechanism between aortas from 2K-1C and 2K rats. Effects of antagonists and inhibitors were investigated on Ang II-induced contractions in denuded or intact-endothelium aortas. The AT1 receptor antagonist abolished Ang II-induced contraction in 2K-1C and 2K rat aortas, while AT2 and Mas receptors antagonists had no effect. Endothelial nitric oxide synthase inhibition increased the maximal effect (Emax) of Ang II in 2K, which was not changed in 2K-1C aortas. It was associated with lower eNOS mRNA levels in 2K-1C. Endothelium removal increased the Emax of Ang II in 2K-1C and mainly in 2K rat aortas. Nox and COX inhibition did not alter Ang II-induced contraction in 2K and 2K-1C rat aortas. However, AT1 expression was higher in 2K-1C compared to 2K rat aortic rings, whereas expression of phosphorylated (active) IP3 receptors was lower in 2K-1C than in 2K rats. These results demonstrate that endothelium removal impairs Ang II-stimulated contraction in the aorta of 2K-1C rats, which is associated with the reduction of IP3 receptor phosphorylation and activation. In addition, eNOS plays a critical role in Ang II-induced contraction in 2K rat aortas. It is possible that the high Ang II plasma levels could desensitize AT1 receptor in 2K-1C rats, leading to impaired IP3 receptors activation.
