Vascul Pharmacol
· 2025 Dec · PMID 40939813
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Pulmonary veno-occlusive disease (PVOD) is a subtype of pulmonary hypertension (PH) with a poor prognosis. Patients with PVOD develop a gradual increase in pulmonary vascular resistance (PVR) and right heart failure. PVO...Pulmonary veno-occlusive disease (PVOD) is a subtype of pulmonary hypertension (PH) with a poor prognosis. Patients with PVOD develop a gradual increase in pulmonary vascular resistance (PVR) and right heart failure. PVOD can occur sporadically (known as sporadic PVOD or sPVOD) or be inherited (known as heritable PVOD or hPVOD). The estimated incidence rate of PVOD is 0.1-0.5 cases per million, which is about ten times less frequent than that of pulmonary artery hypertension (PAH), a condition closely related to PVOD. Because many clinical features of PVOD overlap with those of PAH, PVOD patients are often misdiagnosed as PAH. There is a critical need for early and accurate diagnosis of PVOD and effective therapeutics for PVOD developed based on its underlying etiology. In this review, we highlight the similarities and distinctions between PAH and PVOD, recent advances in understanding the mechanisms of vascular remodeling in PVOD using animal models, and emerging therapeutic strategies specifically targeting PVOD informed by these insights.
Thottapillil N, Corselli M, Murray I
… +13 more, Hardy R, Gomez-Salazar M, Casamitjana J, Shaw I, Wang Z, Vezzani B, Ding L, Deneka A, Guo Y, Giacovazzi S, Crisan M, James A, Péault B
The walls of all embryonic, foetal, and adult blood vessels contain mesodermal progenitors, distributed as pericytes in capillaries and micro vessels, and fibroblastic cells in the tunica adventitia of larger veins and a...The walls of all embryonic, foetal, and adult blood vessels contain mesodermal progenitors, distributed as pericytes in capillaries and micro vessels, and fibroblastic cells in the tunica adventitia of larger veins and arteries. Following dissociation, selection by flow cytometry, and culture, those perivascular cells turn into bona fide mesenchymal stem cells of which they possess all attributes. In vivo, the adventitial cellular niche supports several spatially-organized subsets of mesodermal progenitors biased toward either osteo-, adipo-, or fibrogenesis, and dominated by more primitive, multi-lineage stem-like cells. Experiments in reporter mice have shown that perivascular progenitor cells play roles in tissue scarring, turnover, and regeneration, but also in pathologic fibrosis and vascular remodelling. This review briefly summarizes the phenotypes, anatomical distribution, and developmental capacities of perivascular mesenchymal progenitor cells, underlining the potential interest thereof for cell therapies, tissue engineering, and disease prediction.
Chronic venous disease (CVD) is a prevalent vascular disorder with a poorly characterized genetic basis. In this study, we employed an integrative omics strategy combining genome-wide association studies (GWAS), expressi...Chronic venous disease (CVD) is a prevalent vascular disorder with a poorly characterized genetic basis. In this study, we employed an integrative omics strategy combining genome-wide association studies (GWAS), expression quantitative trait loci (eQTL) mapping, endothelial cell functional assays, and transcriptomic correlation analysis to elucidate the molecular architecture of CVD. A GWAS conducted in a Taiwanese population identified two CVD-associated single nucleotide polymorphisms: VSTM2L rs1998049 and DPYSL2 rs1442887. Through eQTL analysis and endothelial functional assays, four QTLs (VSTM2L, RPRD1B, SAMHD1, and PNMA2) were found to significantly affect VEGF consumption, vWF expression, and endothelial tube formation. Co-expression and correlation analyses further linked these QTLs to key vascular effector genes, including VEGF, vWF, MMP9, and CCM2. A logistic regression model based on QTL expression profiles demonstrated high diagnostic performance (area under the curve, AUC = 0.898), highlighting their translational potential. These findings offer novel insights into the functional genomics of CVD, particularly in relation to vascular remodeling, endothelial dysfunction, and inflammation. They also demonstrate the utility of multi-omics integration for biomarker discovery in complex vascular disorders.
OBJECTIVE: This study evaluates the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on testicular microvascular function and vascular signaling pathways in a swine model of metabolic syndrome (MetS) and isch...OBJECTIVE: This study evaluates the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition on testicular microvascular function and vascular signaling pathways in a swine model of metabolic syndrome (MetS) and ischemic cardiomyopathy (ICM). METHODS: Eleven male Yorkshire swine were fed a high-fat diet to induce MetS. At 11 weeks, ICM was induced by placing an ameroid constrictor around the left circumflex artery. After a two-week stabilization period, swine were randomized into a high-fat control (HFC) or canagliflozin-treated (HCAN, 300 mg/day) group for five weeks. Terminal harvests were performed to assess testicular perfusion, endothelial function markers, and pro-apoptotic signaling. RESULTS: Canagliflozin (CAN) significantly improved testicular perfusion (p = 0.0134). Molecular analysis showed a significant increase in p-AMPK/AMPK ratio (p = 0.0483), indicating enhanced metabolic and endothelial signaling, and a significant reduction in BAD/BCL2 ratio (p = 0.0095), consistent with a shift toward anti-apoptotic signaling. The p-eNOS/eNOS ratio trended upward in treated animals (p = 0.1007), suggesting potential augmentation of nitric oxide-mediated vasodilation. Total ERK expression was also increased (p = 0.0201), supporting engagement of MAPK pathways. CONCLUSION: SGLT2 inhibition improved testicular microvascular perfusion and modulated key signaling ratios, including increased p-AMPK/AMPK and reduced BAD/BCL2, with a trend toward higher p-eNOS/eNOS. These findings demonstrate that canagliflozin promotes vascular survival pathways in peripheral tissues, underscoring its vasculoprotective potential beyond the myocardium.
The heart is an organ that depends significantly on mitochondria to operate, since it requires a lot of energy, which mitochondria create, making them essential for the efficient functioning of the heart. The term "mitoc...The heart is an organ that depends significantly on mitochondria to operate, since it requires a lot of energy, which mitochondria create, making them essential for the efficient functioning of the heart. The term "mitochondrial dynamics" refers to extremely dynamic organelles known as mitochondria that undergo cycles of fusion and fission to modify their appearance, distribution, and function. Drp1 or Dynamin-related protein 1, a primary fission protein, strictly regulates the elimination of damaged mitochondria by mitophagy. This ensures that the complex processes of organ and cellular dynamics in the heart are strictly managed. Phosphorylation, SUMOylation, palmitoylation, ubiquitination, S-nitrosylation, and O-GlcNAcylation are some of the posttranslational modifications (PTMs) of Drp1 that contribute to the regulation of mitochondrial dynamics. While abnormalities in mitochondrial dynamics are a crucial component of the pathophysiology of a number of cardiovascular diseases (CVDs), the heart requires an effective mitochondrial balance to sustain cardiomyocyte metabolism along with contractile activity. This review summarizes the current knowledge of the crucial function of Drp1 inhibitors in the pathophysiology of cardiovascular diseases, including myocardial ischemia-reperfusion, dysfunction of endothelial cells, smooth muscle remodelling, hypertrophy of the heart, high blood pressure, and myocardial infarction. We further highlighted the possible advantages of treating CVDs by specifically targeting Drp1.
Giuliani L, D'Alto M, Di Poi E
… +17 more, Dagna L, Guerra F, Corda M, Perna GP, Doria A, Badagliacca R, Vicenzi M, Airò E, Toma M, Scelsi L, Piccinino C, Brunetti ND, Lombardi CM, Baldi F, Biancospino M, Uglietti A, De Santis S
BACKGROUND: Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a progressive, high-risk subtype of PAH characterized by immune-mediated vascular remodeling, poor treatment response, and red...BACKGROUND: Connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) is a progressive, high-risk subtype of PAH characterized by immune-mediated vascular remodeling, poor treatment response, and reduced survival. Real-world data on therapeutic response and risk evolution in this population remain limited. METHODS: This post hoc analysis of the multicenter, prospective INSPECTIO study evaluated the CTD-PAH subpopulation treated with macitentan and/or selexipag. The primary endpoint was the change in the number of non-invasive low-risk criteria (World Health Organization functional class I-II, 6-min walk distance >440 m, BNP <50 ng/L or NT-proBNP <300 ng/L) from baseline to 12 months. Secondary endpoints included changes in risk stratification, 6MWD, BNP/NT-proBNP levels, echocardiographic and hemodynamic parameters, a comparison with the non-CTD PAH population of the study was also conducted. RESULTS: Among a total of 176 patients enrolled in the INSPECTIO study, 64 (36.4 %) had CTD-PAH. The CTD group, with a larger prevalence of systemic sclerosis (SSc) patients, was predominantly female (93.8 %) and older than the non-CTD group (66.4 vs. 59.6 years, p = 0.0005). The mean number of non-invasive low-risk criteria increased significantly from baseline to Month 12 (+0.20; p = 0.0389), with 10.9 % of CTD patients achieving three low-risk criteria at Month 12. Secondary endpoints (Investigator's risk assessment, 6MWD, BNP, NT-proBNP, echocardiographic and hemodynamic parameters, baseline therapeutic strategy, vital signs) remained collectively stable. CONCLUSIONS: CTD-PAH patients showed improvement in non-invasive risk criteria and stabilization of functional, echocardiographic, and hemodynamic parameters under macitentan and/or selexipag therapy. Despite the observational nature and small sample size, this real-world analysis supports the use of risk-based treatment strategies and close monitoring in this patient population.
Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disorder with no effective drug treatment. Inflammation and macrophage infiltration in the abdominal aorta play a pivotal role in AAA development, prog...Abdominal aortic aneurysm (AAA) is a life-threatening cardiovascular disorder with no effective drug treatment. Inflammation and macrophage infiltration in the abdominal aorta play a pivotal role in AAA development, progression, and rupture. However, the precise molecular mechanisms driving these processes remain unclear. To address this, we analyzed single-cell RNA sequencing datasets from three AAA mouse models and two healthy controls. Our findings revealed that AAA samples showed a marked increase in macrophage populations, with a shift toward pro-inflammatory M1 polarization compared to the predominantly M2 phenotype in controls. CellChat analysis revealed that the STAT1 pathway may mediate the enhanced intercellular communication between M1 and M2 macrophages. SCENIC analysis further identified STAT1 as a central transcriptional regulator in macrophages. We also developed a ten-gene inflammatory signature predictive of AAA prognosis, validated with external datasets, and confirmed STAT1's involvement via Western blotting and real-time PCR. These findings highlight the importance of macrophage polarization and STAT1-driven signaling in AAA pathogenesis. The identified gene signature offers potential for risk stratification and therapeutic targeting, advancing both mechanistic understanding and clinical management of AAA.
Lipscomb M, Salfate Del Rio I, Eid M
… +6 more, Rahtes A, Martino G, Sadhu S, Khan S, MacNamara KC, Fredman G
Vascul Pharmacol
· 2025 Sep · PMID 40759181
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Atherosclerosis is a non-resolving inflammatory disease, and mechanisms to promote inflammation resolution, reduce vascular injury and promote repair in atherosclerosis are unmet needs. Specialized pro-resolving mediator...Atherosclerosis is a non-resolving inflammatory disease, and mechanisms to promote inflammation resolution, reduce vascular injury and promote repair in atherosclerosis are unmet needs. Specialized pro-resolving mediators (SPMs) like Resolvins, in part, mediate inflammation resolution and limit atherosclerosis progression. Uncovering processes associated with their protective actions are of interest. Senescent cells are maladaptive in atherosclerosis, and their accumulation promotes necrotic core formation in plaques. The SPM Resolvin D2 (RvD2) reduces plaque necrosis in part through its G-protein coupled receptor (GPCR), called GPR18. Here, we show how RvD2 can limit senescent cell accumulation in vivo and in vitro. Loss of myeloid GPR18 in Ldlr mice led to increased accumulation of senescent cells, and RvD2 treatment in Ldlr mice led to decreased accumulation of senescent cells in plaques. We found that senescent macrophages are not readily efferocytozed due to elevated "don't eat me" signals called CD24 and CD47. Knockdown or blockade of these signals improved senescent macrophage clearance, but not as efficient as efferocytosis of apoptotic cells in vitro. RvD2 treatment to senescent macrophages in vitro increased Cleaved Caspase-3 (an apoptosis marker) but did not impact the levels of CD24 or CD47. RvD2 enhanced the clearance of senescent macrophages but knockdown or blockade of CD24 and CD47 were also required for efficient clearance. Our work provides a cellular mechanism in which RvD2 treatment may limit plaque necrosis through decreasing senescent macrophages in plaques.
Avagimyan A, Madonna R, Sheibani M
… +21 more, Pogosova N, Trofimenko A, Urazova O, Iop L, Jndoyan Z, Yeranosyan H, Aznauryan A, Sahakyan K, Petrosyan A, Petrosyan R, Tatoyan M, Mkrtchyan G, Sulemaniayants E, Meltonyan G, Kuzniatsou A, Mukherjee R, Rezabakhsh A, Koliakos G, Ottaviani G, Zoccai GB, Sarrafzadegan N
Anthracyclines remain the cornerstone of treatment for malignancies with dose-dependent cardiac damage, ranging from oxidative stress and mitochondrial dysfunction to DNA damage and ferroptosis, and continue to compromis...Anthracyclines remain the cornerstone of treatment for malignancies with dose-dependent cardiac damage, ranging from oxidative stress and mitochondrial dysfunction to DNA damage and ferroptosis, and continue to compromise patient outcome. Animal models, encompassing rodents, rabbits, pigs, and nonhuman primates, are essential for investigating doxorubicin (DOX)-induced cardiovascular toxicity. Acute models facilitate rapid evaluation of cardiac injury; however, they frequently fail to replicate chronic human cardiomyopathy. In contrast, chronic models represent clinical scenarios more accurately but encounter logistical challenges. Species-specific variations in drug metabolism, cardiac physiology, and compensatory mechanisms further complicate the extrapolation. The primary limitations of existing models include the absence of comorbid conditions, lack of combination chemotherapy protocols, and underrepresentation of sex- and age-specific responses. Addressing these challenges is crucial for the development of effective and personalized cardioprotective strategies in cardio-oncology. This review explores the translational challenges of DOX-induced cardiotoxicity, a critical limitation in the development of new cardioprotective strategies in cardio-oncology despite decades of research. We will elucidate the underlying factors that contribute to the difficulties in translating experimental in vivo results into clinical applications.
Angiotensin II (Ang II) increases C3a effects through its receptors, promoting aortic oxidative stress and upregulating matrix metalloproteinase (MMP)-2. MMP-2 is implicated in hypertrophic arterial remodeling in hyperte...Angiotensin II (Ang II) increases C3a effects through its receptors, promoting aortic oxidative stress and upregulating matrix metalloproteinase (MMP)-2. MMP-2 is implicated in hypertrophic arterial remodeling in hypertension. This study investigated whether C3a receptor activation contributes to oxidative stress and increased MMP-2 activity in aortas of Ang II treated mice, ultimately leading to maladaptive vascular changes. Hypertension was induced in C57BL/6 mice via subcutaneous implantation of osmotic mini pumps delivering Ang II (1000 ng/kg/min) for 14 days. Mice were administered the C3aR antagonist, SB290157 (1 mg/kg/day, intraperitoneally) every other day for 14 days. Systolic blood pressure (SBP) and vascular function were assessed via direct blood pressure measurements and contraction and relaxation analysis in a wire myography. Aortic MMP-2 activity was analyzed by gel and in situ zymography. SB290157 did not decrease SBP, aortic hypertrophy or increased aortic reactivity to phenylephrine in Ang II treated mice. Ang II exhibited higher levels of C3a in the plasma and increased tumor necrose factor (TNF)-α and interleukin (IL)-6 in the kidneys (*p < 0.05). SB290157 did not alter C3a, but reduced TNF-α and IL-6 in hypertension (#p < 0.05 vs. Ang II). SB290157 also decreased aortic oxidative stress and p65 factor nuclear kappa B (NFkB) in Ang II treated mice (*p < 0.05). MMP-2 activity was increased in the aortas of Ang II (*p < 0.05) and SB290157 decreased it (*p < 0.05). Pharmacological antagonism of C3a receptor attenuates oxidative stress and MMP-2 activity in the aortas of Ang II treated mice.
Renal hypertension, a common form of secondary hypertension, results from kidney disease. It arises due to the narrowing of arteries connected to the kidneys, often caused by atherosclerosis. Over time, this condition ca...Renal hypertension, a common form of secondary hypertension, results from kidney disease. It arises due to the narrowing of arteries connected to the kidneys, often caused by atherosclerosis. Over time, this condition can lead to kidney failure. Therapeutics for kidney protection are currently limited, prompting continual search for new renoprotective agents in the context of hypertension. Dual blockage of both L-type and T-type calcium channels has shown promise in the treatment of hypertension when compared to selective calcium channel blockers. Toddaculin has been proven to be a potent inhibitor of the T-type channel. Conserved amino acid sequence comparison, electrophysiological recordings, and Flex Station were used to evaluate and compare toddaculin effect on the Ca3.1 and Ca1.2 channels and their respective residues, transiently expressed in HEK293T cells. Intracellular Ca was assessed using the molecular probe fluo-4-AM. They specifically investigated the impact of toddaculin on vascular smooth muscle cells (VSMCs). Toddaculin's myogenic effects were assessed using aortic rings isolated from rats within an organ bath system. In an in vivo context, a mouse model with L-NAME-induced hypertension was employed to investigate toddaculin's anti-hypertensive and renoprotective properties. We found that L1047A in Ca1.2, and L1456A in Ca3.1 are potential key binding sites for toddaculin, and that toddaculin inhibited Ca3.1 and Ca1.2 equally and dose-dependently. Toddaculin-induced decline of [Ca] cultured VSMCs under a laser scanning confocal microscopy. Aortic rings exposed to toddaculin demonstrated dose-dependent relaxation following KCl-induced contraction. Moreover, toddaculin exhibited significant blood pressure reduction and renoprotective effects against L-NAME-induced renal injury in mice. This finding provides an evident therapeutic potential of toddaculin as an antihypertensive drug candidate with a renoprotective effect.
BACKGROUND: Serum lipopolysaccharide (LPS), a marker of gut dysbiosis and endotoxemia is associated with myocardial infarction (MI). We investigated factors affecting LPS changes in MI patients treated with percutaneous...BACKGROUND: Serum lipopolysaccharide (LPS), a marker of gut dysbiosis and endotoxemia is associated with myocardial infarction (MI). We investigated factors affecting LPS changes in MI patients treated with percutaneous coronary intervention (PCI) and aimed to establish factors associated with the degree of LPS decrease following MI. METHODS: In 46 PCI-treated MI patients (mean age 57.2 [8.6]) years we measured LPS and zonulin, a marker of gut permeability, on admission, 30 and 60 days thereafter, inflammatory markers (interleukin [IL]-6, IL-18), P-selectin, and 8-isoprostaglandin F (8-isoPGF). RESULTS: The median initial LPS concentration was 44.0 (37.0-57.0) pg/mL and it fell by 11.3 % at 1 month, with a further 8.3 % drop after the second month, in association with zonulin, but not with P-selectin or inflammatory markers. LPS and zonulin at baseline correlated positively with 8-isoPGF. A < 10 % decrease in LPS was recorded in 20 (43.5 %) patients and was more frequent in smokers, those with a complete occlusion of the infarct-related artery (IRA) and a shorter symptom duration before PCI. LPS decrease <10 % was associated with a decline in IL-10 concentrations 30- and 60-days post MI. On multivariate analysis only current smoking and an initial complete IRA occlusion were independently associated with <10 % decrease in LPS at 1 month (OR 10.44; 95 % CI 2.13-51.21; p = 0.004 and OR 6.59; 95 % CI 1.21-35.88; p = 0.029, respectively). CONCLUSIONS: This study is the first to show factors affecting post-MI changes in LPS, highlighting the role of smoking and initial complete IRA occlusion in persistent low-grade endotoxemia following MI.
Advances in genome annotation have revealed a striking increase in the number and complexity of non-coding RNA (ncRNA) genes, particularly multi-transcript loci that harbor long non-coding RNAs (lncRNAs) and microRNAs (m...Advances in genome annotation have revealed a striking increase in the number and complexity of non-coding RNA (ncRNA) genes, particularly multi-transcript loci that harbor long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) within the same genomic region. These loci can often function as coordinated regulatory units, with their transcription modulated by shared cis-acting regulatory elements (CREs). Traditional gene manipulation approaches, which typically target individual transcripts, are insufficient to capture the full regulatory and therapeutic potential of these complex loci. Here, we present "cis-ON" a single-vector lentiviral delivery system based on CRISPR activation (CRISPRa), designed to simultaneously upregulate multiple noncoding RNA transcripts by targeting a single CRE. We focused on the evolutionarily conserved MIR503HG locus, which encodes seven lncRNA isoforms and hosts the miR-424/503 cluster, both implicated in various cellular processes, including proliferation, angiogenesis, and endothelial-to-mesenchymal transition. Using integrative analysis of histone marks (H3K27Ac, H3K4Me3), DNase hypersensitivity, and CAGE-seq data, we identified the primary promoter of the MIR503HG locus. A dual fluorescent reporter screen selected optimal single guide RNAs (sgRNAs) for targeting this region. We then engineered cis-ON, a novel lentiviral system combining dCas9-VPR and sgRNA to enable a streamlined single-vector delivery approach. Transduction of primary human endothelial cells with this system robustly activated the entire locus including the MIR503HG isoforms and co-embedded miRNAs miR-424 and miR-503, demonstrating coordinated transcriptional regulation. Additionally, the neighboring LINC00629 lncRNA locus remained unaffected, highlighting regulatory specificity. This approach demonstrates the feasibility of modulating complex ncRNA loci across a ∼ 10 kb genomic region by targeting a single CRE, bypassing limitations of transcriptspecific strategies. By enabling simultaneous upregulation of lncRNAs and miRNAs, the cis-ON platform provides a streamlined strategy for restoring regulatory networks disrupted in disease.
INTRODUCTION: Pulmonary arterial hypertension (PAH) remains a life-threatening condition characterized by high morbidity and mortality. However, recent therapeutic advancements have offered a paradigm shift in terms of t...INTRODUCTION: Pulmonary arterial hypertension (PAH) remains a life-threatening condition characterized by high morbidity and mortality. However, recent therapeutic advancements have offered a paradigm shift in terms of therapeutic goals. METHODS: We conducted a systematic review and meta-analysis of RCTs assessing clinical outcomes and safety of sotatercept when compared to placebo in PAH. Searches of Pubmed and Cochrane Central databases were performed through April 2025. The primary outcome was all-cause mortality. Secondary outcomes included improvements in 6MWD, WHO functional class, hemodynamics, NT-proBNP, and serious adverse events. Data were pooled using a random-effects model, with certainty of evidence assessed via GRADE methodology. RESULTS: Three RCTs comprising 601 patients were included. There was a non-significant trend toward reduced mortality (RR 0.49; 95 % CI 0.16 to 1.46; p = 0.11). Sotatercept was associated with significant improvements in 6MWD (MD 37.99 m; 95 % CI 6.47 to 69.52; p = 0.04) and WHO functional class (RR 2.04; 95 % CI 1.79 to 2.31; p = 0.002). Hemodynamic improvements included reductions in PVR (MD -237.73 dyn·s/cm; 95 % CI -367.02 to -1.8.43; p = 0.02) and mPAP (MD -14.88 mmHg; 95 % CI -24.76 to -4.99; p = 0.02). Serious adverse events were similar (RR 0.79; 95 % CI 0.51 to 1.23; p = 0.15). CONCLUSION: Sotatercept significantly improves functional and hemodynamic outcomes in PAH, with a favorable safety profile. While mortality benefits remain uncertain, these findings support its clinical utility as an emerging therapy in PAH.
Pulmonary hypertension is a progressive vascular disease characterized by pulmonary vascular remodeling, with high mortality and poor prognosis despite advances in medical therapy. Recently, histone modification therapie...Pulmonary hypertension is a progressive vascular disease characterized by pulmonary vascular remodeling, with high mortality and poor prognosis despite advances in medical therapy. Recently, histone modification therapies for pulmonary hypertension have received more attention. Studies have shown that abnormal histone modifications and the enzymes responsible for these alterations can drive pulmonary vascular cell proliferation, migration, and anti-apoptosis by regulating chromatin structure and gene expression, thereby promoting pulmonary vascular remodeling in pulmonary hypertension. This review illustrates histone modifications, including methylation, acetylation, lactylation, and SUMOylation, and the enzymes responsible for these modifications, exploring their role and pathophysiological mechanism in pulmonary hypertension. In addition, the review summarizes the small molecule modulators currently under development and their efficacy in various preclinical models of pulmonary hypertension. Comprehending the function of histone modifications in pulmonary hypertension will help identify new biomarkers and molecular targets and facilitate personalized treatments for this severe disease.
Good leptomeningeal collateral vessels (LMC) are associated with smaller lesion volume and better patient outcomes from ischaemic stroke, but their architecture varies greatly between individuals. Statins can stimulate a...Good leptomeningeal collateral vessels (LMC) are associated with smaller lesion volume and better patient outcomes from ischaemic stroke, but their architecture varies greatly between individuals. Statins can stimulate angiogenesis and show promise for stimulating cerebral collaterogenesis. Statins could thus improve LMC grade and ensure all patients receive positive outcomes from treatment. This potentially explains why statin treatment is effective given prior to stroke in pre-clinical models, but not prescribed afterwards in clinical trials. LMC-rich C57Bl/6 and LMC-poor BALB/c 12-week-old male mice were randomised to receive daily oral simvastatin (10 mg/kg) or vehicle for 4 weeks. The cerebrovasculature was silicone-perfused, allowing LMC numbers and dimensions to be analysed. Values for tortuosity, vascularity and LMC resistance were calculated. In BALB/c, estimated resistance was lower with simvastatin treatment (vehicle: 0.104 ± 0.09, simvastatin: 0.023 ± 0.02; p = 0.04) and LMC numbers were greater (vehicle: 1.6 ± 1.6, simvastatin: 4.0 ± 3.2; p = 0.04). In C57Bl/6, there was no difference to resistance, but LMCs were smaller in diameter (vehicle: 16.3 ± 1.8 μm, simvastatin: 14.0 ± 1.4 μm, p = 0.008). Statin-treated C57Bl/6 also had more arterial branchpoints (left hemisphere, vehicle: 363.8 ± 55 per cm2, simvastatin: 417.3 ± 58 per cm2, p = 0.007; right, vehicle: 315.1 ± 40 per cm2, simvastatin: 397.5 ± 43 per cm2, p < 0.0001). We have observed signs of collaterogenesis and angiogenesis, providing evidence that statins stimulate growth of LMCs. Greatest benefit was seen in LMC-poor BALB/c, suggesting that patients with poor LMC circulation stand to gain most from LMC-enhancing therapies. Patients receiving statins prior to stroke have likely developed better LMCs, leading to better stroke outcomes. These findings should stimulate investigation of further safe, widely-available LMC-enhancing therapies.
For over 150 years, nitrates have been a cornerstone in the treatment of cardiovascular disease. Nitroglycerin - synthesized by Italian chemist Ascanio Sobrero in 1847 - was initially used in explosives, as the main comp...For over 150 years, nitrates have been a cornerstone in the treatment of cardiovascular disease. Nitroglycerin - synthesized by Italian chemist Ascanio Sobrero in 1847 - was initially used in explosives, as the main component of dynamite, by Alfred Nobel. The Scottish physician Lauder Brunton first used amyl nitrite for angina in 1867, and in 1879 the English physician William Murrell described the benefits of nitroglycerin for angina pectoris. Organic nitrates, including nitroglycerin, act as nitric oxide donors, sharing the mechanism of NO release, which induces vasodilation. This paper reviews the fascinating history of nitroglycerin and nitroderivatives, the related discovery of nitric oxide as a cardiovascular signaling molecule, and the 1998 Nobel Prize awarded for this discovery. The paper also succinctly explores current and future roles of nitric oxide donors in cardiovascular treatment.
Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide, driven by complex interactions among various plaque cell types, including endothelial cells, macrophages, and smooth muscle cells. T...Atherosclerosis is a leading cause of cardiovascular morbidity and mortality worldwide, driven by complex interactions among various plaque cell types, including endothelial cells, macrophages, and smooth muscle cells. Traditional therapies targeting systemic risk factors such as cholesterol and blood pressure fail to directly address the underlying mechanisms governing plaque formation and progression. Recent advances in cell-specific therapies offer new avenues for targeting the cellular and molecular processes driving atherosclerosis. This Review explores innovative strategies including nanoparticles, viral vectors and CRISPR-Cas9 technology, which have the potential to modulate gene expression and behaviour within plaques cells to alleviate disease. By focusing on the specific roles of key cell types in atherosclerosis, these emerging therapies promise to provide more precise, effective, and personalised treatment options without inducing off-target effects. Moreover, insights gained from successful applications of these technologies in oncology are considered for potential repurposing in atherosclerosis-related disease. As these cell-specific approaches advance through preclinical and clinical development, they may significantly enhance our ability to treat atherosclerosis at its cellular roots, offering new hope for reducing the burden of cardiovascular disease.