We previously reported pulmonary arterial remodelling and active endothelial to mesenchymal transition (EndMT) in smokers and patients with early COPD. In this study, we aimed to evaluate the role of different drivers of EndMT. Immunohistochemical staining for EndMT drivers, TGF-β1, pSMAD-2/3, SMAD-7, and β-catenin, was performed on lung resections from 46 subjects. Twelve were non-smoker-controls (NC), six normal lung function smokers (NLFS), nine patients with small-airway diseases (SAD), nine mild-moderate COPD-current smokers (COPD-CS) and ten COPD-ex-smokers (COPD-ES). Histopathological measurements were done using Image ProPlus softwarev7.0. We observed lower levels of total TGF-β1 (p<0.05) in all smoking groups than in the non-smoking control (NC). Across arterial sizes, smoking groups exhibited significantly higher (p <0.05) total and individual layer pSMAD-2/3 and SMAD-7 than in the NC group. The ratio of SAMD-7 to pSMAD-2/3 was higher in COPD patients compared to NC. Total β-catenin expression was significantly higher in smoking groups across arterial sizes (p <0.05), except for COPD-ES and NLFS groups in small and medium arteries, respectively. Increased total β-catenin was positively correlated with total S100A4 in small and medium arteries (r= 0.35, 0.50; p=0.02, 0.01, respectively), with vimentin in medium arteries (r=0.42, p=0.07), and with arterial thickness of medium and large arteries (r= 0.34, 0.41, p=0.02, 0.01, respectively). This is the first study uncovering active endothelial SMAD pathway independent of TGF-β1 in smokers, SAD, and COPD patients. Increased expression of β-catenin indicates its potential interaction with SMAD pathway, warranting further research to identify the deviation of this classical pathway.

OBJECTIVE: Calciprotein particles (CPPs) are circulating calcium and phosphate nanoparticles associated with development of vascular calcification (VC) in chronic kidney disease (CKD). Although recent studies have been focusing on associations of CPPs with presence of VC in CKD, insights in the underlying processes and mechanisms by which CPPs might aggravate VC and vascular dysfunction in vivo are currently lacking. Here, we assessed overall burden of abdominal VC in healthy kidney donors and CKD patients, and subsequently performed transcriptome profiling in vascular tissue obtained from these subjects, linking outcome to CPP counts and calcification propensity.
RESULTS: Calcification scores were quantified in renal arteries, iliac arteries and abdominal aorta, using computed tomography (CT) scans of kidney donors and CKD patients. Vascular tissue was collected from kidney donors (renal artery) and CKD patients (iliac artery), after which bulk RNA sequencing and gene set enrichment analysis (GSEA) was performed on a subset of patients. Calcification propensity (crystallization time, T50) was measured using nephelometry, and CPP counts with microparticle flow cytometric analysis. Increased calcification scores (based on CT) were found in CKD patients compared to kidney donors. Transcriptome profiling revealed enrichment for processes related to endothelial activation, inflammation, extracellular matrix (ECM) remodelling and ossification in CKD vascular biopsies compared to kidney donors. Calcification propensity was increased in CKD, as well as CPP counts, of which the latter significantly associated with markers of vascular remodelling.
CONCLUSIONS: Our findings reveal that CKD is characterized by systemic VC with increased calcification propensity and CPP counts. Transcriptome profiling showed altered vascular gene expression with enrichment for endothelial activation, inflammation, ECM remodelling and ossification. Moreover, we demonstrate for the first time that vascular remodelling processes are associated with increased circulating CPP counts. Interventions targeting CPPs are promising avenues for alleviating vascular remodelling and VC in CKD.

Optimal vascular structure and function are essential for maintaining the physiological functions of the cardiovascular system. Vascular remodelling involves changes in vessel structure, including its size, shape, cellular and molecular composition. These changes result from multiple risk factors and may be compensatory adaptations to sustain blood vessel function. They occur in diverse cardiovascular pathologies, from hypertension to heart failure and atherosclerosis. Dynamic changes in the endothelium, fibroblasts, smooth muscle cells, pericytes or other vascular wall cells underlie remodelling. In addition, immune cells, including macrophages and lymphocytes, may infiltrate vessels and initiate inflammatory signalling. They contribute to a dynamic interplay between cell proliferation, apoptosis, migration, inflammation, and extracellular matrix reorganisation, all critical mechanisms of vascular remodelling. Molecular pathways underlying these processes include growth factors (e.g., vascular endothelial growth factor and platelet-derived growth factor), inflammatory cytokines (e.g., interleukin-1β and tumour necrosis factor-α), reactive oxygen species, and signalling pathways, such as Rho/ROCK, MAPK, and TGF-β/Smad, related to nitric oxide and superoxide biology. MicroRNAs and long noncoding RNAs are crucial epigenetic regulators of gene expression in vascular remodelling. We evaluate these pathways for potential therapeutic targeting from a clinical translational perspective. In summary, vascular remodelling, a coordinated modification of vascular structure and function, is crucial in cardiovascular disease pathology.

UNASSIGNED: To document vascular changes in eyes with post-fever retinitis (PFR) pre and post treatment demonstrated using optical coherence tomography angiography (OCTA).
UNASSIGNED: This is a retrospective observational case series wherein patients with PFR were retrospectively evaluated for changes in the retinal vasculature during the course of disease using OCTA.
UNASSIGNED: At presentation, OCTA revealed flow void areas in superficial and deep capillary plexus (SCP and DCP) corresponding to the areas of retinitis. Post treatment, OCTA showed a significant decrease in the flow void areas with the appearance of new capillary network in both SCP and DCP. The optical coherence tomography also demonstrated normalization of retinal architecture over time. It is speculated that the good visual outcome in PFR could be attributed to the normalization of retinal architecture and remodelling in retinal vasculature.
UNASSIGNED: OCTA being non-invasive can be used to understand and quantify the extent of vascular remodelling in PFR.

In the seemingly well-researched field of vascular research, there are still many underestimated factors and molecular mechanisms. In recent years, SUMOylation has become increasingly important. SUMOylation is a post-translational modification in which small ubiquitin-related modifiers (SUMO) are covalently attached to target proteins. Sites where these SUMO modification processes take place in the cell nucleus are PML nuclear bodies (PML-NBs) - multiprotein complexes with their essential main component and organizer, the PML protein. PML and SUMO, either alone or as partners, influence a variety of cellular processes, including regulation of transcription, senescence, DNA damage response and defence against microorganisms, and are involved in innate immunity and inflammatory responses. They also play an important role in maintaining homeostasis in the vascular system and in pathological processes leading to the development and progression of cardiovascular diseases. This review summarizes information about the function of SUMO(ylation) and PML(-NBs) in the human vasculature from angiogenesis to disease and highlights their clinical potential as drug targets.

Background: We have previously reported that endothelial-to-mesenchymal transition (EndMT) is an active process in patients with idiopathic pulmonary fibrosis (IPF) contributing to arterial remodelling. Here, we aim to quantify drivers of EndMT in IPF patients compared to normal controls (NCs). Methods: Lung resections from thirteen IPF patients and eleven NCs were immunohistochemically stained for EndMT drivers, including TGF-β1, pSmad-2/3, Smad-7, and β-catenin. Intima, media, and adventitia were analysed for expression of each EndMT driver in pulmonary arteries. Computer- and microscope-assisted Image ProPlus7.0 image analysis software was used for quantifications. Results: Significant TGF-β1, pSmad-2/3, Smad-7, and β-catenin expression was apparent across all arterial sizes in IPF (p < 0.05). Intimal TGF-β1, pSmad-2/3, Smad-7, and β-catenin were augmented in the arterial range of 100-1000 μm (p < 0.001) compared to NC. Intimal TGF-β1 and β-catenin percentage expression showed a strong correlation with the percentage expression of intimal vimentin (r\' = 0.54, p = 0.05 and r\' = 0.61, p = 0.02, respectively) and intimal N-cadherin (r\' = 0.62, p = 0.03 and r\' = 0.70, p = 0.001, respectively). Intimal TGF-β1 and β-catenin expression were significantly correlated with increased intimal thickness as well (r\' = 0.52, p = 0.04; r\' = 0.052, p = 0.04, respectively). Moreover, intimal TGF-β1 expression was also significantly associated with increased intimal elastin deposition (r\' = 0.79, p = 0.002). Furthermore, total TGF-β1 expression significantly impacted the percentage of DLCO (r\' = -0.61, p = 0.03). Conclusions: This is the first study to illustrate the involvement of active TGF-β/Smad-2/3-dependent and β-catenin-dependent Wnt signalling pathways in driving EndMT and resultant pulmonary arterial remodelling in patients with IPF. EndMT is a potential therapeutic target for vascular remodelling and fibrosis in general in patients with IPF.

Diseases of the central nervous system (CNS) are often associated with vascular disturbances or inflammation and frequently both. Consequently, endothelial cells and macrophages are key cellular players that mediate pathology in many CNS diseases. Macrophages in the brain consist of the CNS-associated macrophages (CAMs) [also referred to as border-associated macrophages (BAMs)] and microglia, both of which are close neighbours or even form direct contacts with endothelial cells in microvessels. Recent progress has revealed that different macrophage populations in the CNS and a subset of brain endothelial cells are derived from the same erythromyeloid progenitor cells. Macrophages and endothelial cells share several common features in their life cycle-from invasion into the CNS early during embryonic development and proliferation in the CNS, to their demise. In adults, microglia and CAMs have been implicated in regulating the patency and diameter of vessels, blood flow, the tightness of the blood-brain barrier, the removal of vascular calcification, and the life-time of brain endothelial cells. Conversely, CNS endothelial cells may affect the polarization and activation state of myeloid populations. The molecular mechanisms governing the pas de deux of brain macrophages and endothelial cells are beginning to be deciphered and will be reviewed here.

BACKGROUND: Intracranial atherosclerosis, a leading cause of stroke, involves arterial plaque formation. This study explores the link between plaque remodelling patterns and diabetes using high-resolution vessel wall imaging (HR-VWI).
OBJECTIVE: To investigate the factors of intracranial atherosclerotic remodelling patterns and the relationship between intracranial atherosclerotic remodelling and diabetes mellitus using HR-VWI.
METHODS: Ninety-four patients diagnosed with middle cerebral artery or basilar artery atherosclerosis were enrolled. Their basic clinical data were collected, and HR-VWI was performed. The vascular area at the plaque (VAMLN) and normal reference vessel (VAreference) were delineated and measured using image postprocessing software, and the Remodelling index (RI) was calculated. According to the value of the RI, the patients were divided into a positive remodelling (PR) group, intermediate remodelling (IR) group, negative remodelling (NR) group, PR group and non-PR (N-PR) group.
RESULTS: The PR group exhibited a higher prevalence of diabetes and serum cholesterol levels than the IR and NR groups [45.2%, 4.54 (4.16, 5.93) vs 25%, 4.80 ± 1.22 and 16.4%, 4.14 (3.53, 4.75), respectively, P < 0.05]. The diabetes incidence was also significantly greater in the PR group than in the N-PR group (45.2% vs 17.5%, P < 0.05). Furthermore, the PR group displayed elevated serum triglyceride and cholesterol levels compared to the N-PR group [1.64 (1.23, 2.33) and 4.54 (4.16, 5.93) vs 4.54 (4.16, 5.93) and 4.24 (3.53, 4.89), P < 0.05]. Logistic regression analysis revealed diabetes mellitus as an independent influencing factor in plaque-PR [odds ratio (95% confidence interval): 3.718 (1.207-11.454), P < 0.05].
CONCLUSIONS: HR-VWI can clearly show the morphology and signal characteristics of intracranial vascular walls and plaques. Intracranial atherosclerotic plaques in diabetic patients are more likely to show PR, suggesting poor plaque stability and a greater risk of stroke.

Pulmonary arterial hypertension (PAH) is characterized by extensive pulmonary arterial remodelling. Although mesenchymal stem cell (MSC)-derived exosomes provide protective effects in PAH, MSCs exhibit limited senescence during in vitro expansion compared with the induced pluripotent stem cells (iPSCs). Moreover, the exact mechanism is not known.
In this study, we used murine iPSCs generated from mouse embryonic fibroblasts with triple factor (Oct4, Klf4, and Sox2) transduction to determine the efficacy and action mechanism of iPSC-derived exosomes (iPSC-Exo) in attenuating PAH in rats with monocrotaline (MCT)-induced pulmonary hypertension. Both early and late iPSC-Exo treatment effectively prevented the wall thickening and muscularization of pulmonary arterioles, improved the right ventricular systolic pressure, and alleviated the right ventricular hypertrophy in MCT-induced PAH rats. Pulmonary artery smooth muscle cells (PASMC) derived from MCT-treated rats (MCT-PASMC) developed more proliferative and pro-migratory phenotypes, which were attenuated by the iPSC-Exo treatment. Moreover, the proliferation and migration of MCT-PASMC were reduced by iPSC-Exo with suppression of PCNA, cyclin D1, MMP-1, and MMP-10, which are mediated via the HIF-1α and P21-activated kinase 1/AKT/Runx2 pathways.
IPSC-Exo are effective at reversing pulmonary hypertension by reducing pulmonary vascular remodelling and may provide an iPSC-free therapy for the treatment of PAH.

Arteriovenous malformation (AVM) is an anomaly of blood vessel formation. Numerous models have been established to understand the nature of AVM. These models have limitations in terms of the diameter of the vessels used and the impact on the circulatory system. Our goal was to establish an AVM model that does not cause prompt and significant hemodynamic and cardiac alterations but is feasible for follow-up of the AVM\'s progression. Sixteen female rats were randomly divided into sham-operated and AVM groups. In the AVM group, the saphenous vein and artery were interconnected using microsurgical techniques. The animals were followed up for 12 weeks. Anastomosis patency and the structural and hemodynamic changes of the heart were monitored. The hearts and vessels were histologically analyzed. During the follow-up period, shunts remained unobstructed. Systolic, diastolic, mean arterial pressure, and heart rate values slightly and non-significantly decreased in the AVM group. Echocardiogram results indicated minor systolic function impact, with slight and insignificant changes in aortic pressure and blood velocity, and minimal left ventricular wall enlargement. The small-caliber saphenous AVM model does not cause acute hemodynamic changes. Moderate but progressive alterations and venous dilatation confirmed AVM-like features. The model seems to be suitable for studying further the progression, enlargement, or destabilization of AVM.