Hydrogen sulfide (H2S) is a gaseous signalling molecule with vasodilatory properties and regulates inflammation and fibrosis in the liver. Rats with bile duct ligation-induced liver disease were treated with propargylglycine (PAG; 30 mg/kg via intragastric gavage), a selective inhibitor of cystathionine γ-lyase, the main source of H2S in the cardiovascular system and liver, or vehicle. PAG treatment was initiated at day 5 after BDL to evaluate its effects on the progression of liver fibrosis and portal hypertension. In BDL rats, PAG significantly reduced portal pressure (10.4 ± 2.7 mmHg versus 16.0 ± 3.9 mmHg, P < 0.05) without affecting systemic pressure. In mesenteric arteries mounted on a wire myograph, no differences were observed in responses to acetylcholine and H2S donor sodium hydrosulfide between treated and untreated BDL rats. In the liver, PAG treatment significantly reduced the expression of IL-6, TGFβ, and collagen I, and markedly attenuated hepatic fibrosis and architectural distortion. Rats treated with PAG also exhibited significantly lower alanine aminotransferase. In conclusion, in BDL rats, inhibition of H2S synthesis decreases portal pressure and attenuates liver fibrosis, suggesting that targeting H2S may represent a therapeutic strategy for portal hypertension, potentially through modulation of intrahepatic resistance.

BAG3 (Bcl-2 associated athanogene 3) is a multifunctional protein with pleiotropic effects in multiple cell types. Despite our knowledge of its role in cardiovascular disease, its specific role in endothelial cells (ECs) is unknown. The purpose of this study was to identify differences in the EC proteome of multiple tissues before and after cell specific deletion of Bag3. We hypothesized that BAG3 loss would uniquely alter the baseline proteome landscape of ECs in each tissue. Cdh5(PAC)-CreERT2;Bag3f/f mice received tamoxifen (KO; n=18) or vehicle (WT; n=18) and tissues (brain, heart, lung, and peripheral skeletal muscle-SkM) were collected for FACS of ECs from equal numbers of male and female mice at >22 weeks of age, followed by LC-MS/MS label-free proteomics. Initial comparisons of the WT proteomes between tissues revealed differential abundance of EC proteins (p<0.05), including: 367 brain v heart; 338 brain v lung; 570 brain v SkM; 400 heart v lung; 104 heart v SkM; and 489 lung v SkM. Additionally, the EC mitochondrial proteome was unique to each tissue of origin, with significantly (p<0.05) higher proportions dedicated to complexes I, III, IV and V, in heart compared to the other tissues. KO demonstrated the largest effect on SkM ECs, increasing 31 proteins (Mybpc2 Log2FC=4.81; PFKM Log2FC=3.02) and decreasing 65 (CDC42 Log2FC=-2.44; Prpf8 Log2FC=-2.24). Overall, these results demonstrate that the EC proteome of different tissues is unique and that the loss of BAG3 in these cells differentially alters a small proportion of the EC specific proteome.

Hypertension is a major risk factor for cardiovascular disease, yet its effects on the retinal microvasculature in women, independent of pregnancy and diabetes, remain poorly understood. We integrated retinal imaging in female participants with structural assessments in hypertensive female mice to evaluate retinal microvascular remodeling. In women, higher systolic blood pressure was associated with reduced retinal arteriolar area and retinal thinning, independent of BMI or glycemic status. Women over age 50 exhibited greater retinal microvascular loss, suggesting age-related susceptibility. After adjusting for age, retinal arteriolar area remained significantly associated with hypertension, whereas venular area and retinal thickness were primarily associated with age. No significant age x hypertension interactions were observed for any outcome. In parallel, hypertensive BPH/2J mice displayed retinal microvascular rarefaction and reduced pericyte coverage compared with normotensive BPN/3J controls. Across species, hypertension induced rarefaction, arteriolar loss, and pericyte depletion, indicating impaired microvascular integrity. These findings support the utility of retinal imaging as a noninvasive biomarker of hypertensive microvascular disease in women.

Numerous studies have identified various miRNAs involved in aortic aneurysm pathology. This study investigates circulating miRNAs before and after abdominal aortic aneurysm repair (open surgical repair [OSR] or endovascular aneurysm repair [EVAR]). In this prospective, non-randomized, two-arm study, all eligible patients who underwent elective surgery from 2019 to 2021 for infrarenal aortic aneurysm were enrolled. Preoperative, postoperative (day 3), and follow-up serum samples (3 and 12 months) were collected. Circulating miR-29b/29c, miR-155, and miR-15a were analyzed using RT-qPCR. A total of 39 patients (87.2% male) were enrolled (Group I: OSR, n=17; Group II: EVAR, n=22). There were no significant differences in the expression of circulating miR-155, miR-15a, miR-29b, or miR-29c between Groups I and II during follow-up. However, subgroup analysis showed significantly lower expression of miR-15a in EVAR patients without an endoleak compared to those with an endoleak, as well as in patients undergoing open repair in the early postoperative phase (day 3). Our study found no significant differences in the expression of miR-155, miR-15a, miR-29b, or miR-29c before and after aneurysm repair, regardless of the surgical approach. However, early postoperative expression of miR-15a was significantly lower in EVAR patients without an endoleak, suggesting a potential role for miR-15a in early aortic remodeling following EVAR.

Vascular calcification (VC) is a frequent complication in diabetes and is linked to an increased risk of thrombotic cardiovascular events. Diabetes is characterized by impaired fibrinolysis, and accumulating evidence implicates fibrin deposition in VC progression. However, how fibrinolytic dysregulation contributes to VC remains unclear. We examined the role of fibrinolytic factors in VC using an established in vitro model. Vascular smooth muscle cells were cultured under high glucose conditions to evaluate glucose-induced VC and plasminogen activator inhibitor-1 (PAI-1) expression. In addition, exogenous plasmin stimulation was performed to assess its effects on VC progression and anti-calcific signaling. High glucose enhanced VC and markedly increased PAI-1 expression. Inhibition of PAI-1 signaling attenuated glucose-induced VC, indicating its involvement in VC development under hyperglycemia. Conversely, exogenous plasmin reduced VC under normoglycemic conditions. Short-term plasmin stimulation activated AMP-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS), both known inhibitors of VC. These findings suggest that PAI-1 contributes to hyperglycemia-related VC, whereas plasmin exerts protective effects partly through AMPK-eNOS activation. Modulating plasmin activity or targeting PAI-1 may represent potential therapeutic approaches to prevent VC progression in diabetes.

Arterial insufficiency is a key factor in chronic wounds, diabetes, and peripheral arterial disease, all of which impair vascular function. Accurate monitoring of tissue-level oxygenation and hemodynamics is critical for assessing outcomes in cases of vascular compromise. However, many existing tools only measure small, localized regions of tissue. This study evaluates spatial variation in oxygenation during a vascular occlusion test (VOT) using a wide-field imaging using spatial frequency domain imaging (SFDI). Tissue oxygenation and perfusion dynamics were assessed using SFDI to map oxygen saturation (StO₂), total hemoglobin in the papillary dermis (HbT1), and deeper tissue (HbT2) during a vascular occlusion test (VOT) in 13 subjects. Measurements were taken immediately before induction of the occlusion, after 4 minutes of occlusion and immediately after occlusion release. Two regions of interest (ROIs) were analyzed: 1) areas with larger subsurface vessels (macrovasculature), and 2) areas dominated by capillary networks (microvasculature). StO₂ values differed significantly between microvascular-only and macrovascular ROIs at all time points. Microvascular ROIs showed greater StO₂ changes during occlusion, indicating higher oxygen extraction. HbT1 concentrations did not differ significantly between ROIs at any time point. Spatial variation is critical when comparing tissue hemodynamics across time and subjects. Non-contact wide-field imaging enables assessment of heterogeneous tissue regions that are difficult to evaluate with probe-based methods.

Introduction: Hydroxychloroquine (HCQ) has been associated with lower incidence of cardiovascular events in patients with autoimmune diseases and atherosclerosis progression in mouse models. Our study aimed at investigating the effect of HCQ on autophagy and neutrophil extracellular trap (NET) formation in aortas of ApoE−/− mice. Methods: ApoE−/− mice were treated with 10 mg/kg/day HCQ for 16 weeks. The aortas were examined histologically, while immunofluorescence staining and confocal microscopy were performed to identify the co-localization of myeloperoxidase (MPO) with DNA or microtubule-associated protein 1A/1B-light chain 3B (LC3B) as markers of NET formation and autophagy, respectively. Results: Among 52 ApoE−/− mice (30 male, 22 female), HCQ was administered in 15 male and 12 female mice. HCQ was associated with a significant reduction of the mean (±SD) surface of the atherosclerotic plaque compared to controls (HCQ-treated vs. control, 0.04 ± 0.01 mm2 vs. 0.08 ± 0.04 mm2, p < 0.01 and 0.06 ± 0.04 mm2 vs. 0.15 ± 0.09 mm2, p = 0.012, for male and female, respectively). This reduction was associated with a significant attenuation in the mean fluorescence intensity of MPO and LC3B expression in the atherosclerotic plaque of HCQ-treated mice (p = 0.03 and p = 0.01, respectively). In line with these findings, HCQ significantly reduced the proportion of MPO+ and LC3B+ cells within the atherosclerotic lesions. Conclusions: HCQ administration in ApoE−/− mice may mitigate the progression of atherosclerotic plaque, by inhibiting autophagy and NET formation.

Angiotensin converting enzyme (ACE) regulates blood pressure via the renin-angiotensin and bradykinin systems. Though synthetic ACE inhibitors are more effective, they pose several side effects. Methyl palmitate (MP), a natural fatty acid methyl ester with cytoprotective, antioxidant, anti-inflammatory, and vasodilatory properties, is not explored for its ACE inhibitory or antihypertensive potential. This study aimed to investigate the in vitro ACE inhibition of MP and its effect on L-NG-Nitro Arginine Methyl Ester (<sc>L</sc>-NAME)-induced hypertensive male Wistar rats. An in vitro ACE inhibition assay was conducted to compare the inhibition potency of MP with that of lisinopril. Male Wistar rats (n = 35, 7 per group) were grouped into control, disease control, and treatment groups receiving 100, 150, or 200 mg/kg/day of MP for 21 days each. Blood pressure, serum ACE activity, malondialdehyde (MDA), and nitric oxide (NO) levels in kidney tissue homogenate, and thoracic aorta histopathology were assessed. MP inhibited ACE by 61.05% at 5 µ<sc>m</sc>, exceeding lisinopril's 41.67%. High-dose MP significantly reduced serum ACE and MDA levels, while increasing NO (p < 0.001). Histopathology revealed near-normal vasculature, although changes in blood pressure were not statistically significant (p > 0.05). MP demonstrates strong natural ACE inhibition, antioxidant, and vascular protective effects, supporting further research for therapeutic optimization.

Introduction: The vessels of different organs may demonstrate functional heterogeneity depending on organ they supply. However, few works systematically examine arteries of different organs. We hypothesized that arteries of different organs will demonstrate different passive pressure-diameter responses and functional responses to contractile and dilatory agonists. Methods: Mesenteric, sural, interlobar renal, basilar, and septal coronary arteries of Wistar rats were studied using wire myography. Results: Sural and coronary arteries had a slightly smaller diameter compared to other studied vessels. Passive elastic characteristics of the studied vessels were similar. Only sural and basilar arteries tended to develop considerable stretch-induced tone. Mesenteric, sural, and renal arteries demonstrated similar maximum contractile response to agonist of α1-adrenoceptors methoxamine, while mesenteric arteries showed the lowest sensitivity to this agonist. The maximum contractile response and sensitivity of basilar artery to thromboxane A2 analog U46619 were higher compared to coronary arteries. The smallest amplitude of maximum relaxation to acetylcholine was found for renal artery. Conclusion: Our data demonstrate that even general characteristics of arteries like stretch-induced tone, sensitivity to contractile and dilatory agonists vary between the arteries of comparable caliber, but from different organs.

Plain Language SummaryThis review looks at several common health conditions that increase the risk of heart disease. These include metabolic syndrome (a group of risk factors like high blood pressure and high blood sugar often linked to obesity), the hypertriglyceridemic waist (a condition where a person has both a large waist and high levels of fats in the blood), fatty liver disease caused by metabolism problems, cardiorenometabolic syndrome (a condition that affects the heart, kidneys, and metabolism), and polycystic ovary syndrome (a hormonal condition in women that often causes weight gain and irregular periods). Although these conditions are different, they share similar biological problems, such as insulin resistance (when the body does not use insulin effectively), inflammation, and abnormal fat levels in the blood. These shared problems help explain why people with these conditions are more likely to develop heart disease. The review suggests that doctors should look at these conditions together rather than separately. Doing this could help identify people at risk earlier. New tools like specific blood tests, body scans, or genetic analysis could help tailor treatments to each patient. A treatment plan should be based on the person’s unique health profile, with a mix of lifestyle changes, medications, and regular follow-up. Understanding how these conditions are linked can help improve care, reduce heart disease risk, and lead to better health overall. The goal is to act early and use personalised strategies to manage risk before serious problems occur.