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Background: Obesity, a major risk factor for cardiovascular disease (CVD), is associated with hypertension and vascular dysfunction. Perivascular adipose tissue (PVAT), a metabolically active tissue surrounding blood vessels, plays a key role in regulating vascular tone. In obesity, PVAT becomes dysregulated which may contribute to vascular dysfunction; how sex impacts the remodelling of PVAT and thus the altered vascular contractility during obesity is unclear. Objective: To investigate sex-specific PVAT dysregulation in the setting of obesity as a potential driver of sex differences in vascular pathologies and CVD risk. Methods: Adult male and female C57Bl/6J mice were fed an obesogenic high-fat diet (HFD) or regular chow for 16 weeks. Mesenteric PVAT (mPVAT) was isolated for RNA-sequencing and histological analysis, and mesenteric arteries were isolated for assessment of vascular function by wire myography. In a separate study, female mice were subjected to bilateral ovariectomy prior to dietary intervention to determine the contribution of ovarian hormones to PVAT dysregulation. Results: Transcriptomic analysis of mPVAT revealed sexually dimorphic responses to HFD, with upregulation of extracellular matrix (ECM) remodelling pathways in male but not female mice. Histological and RT-qPCR approaches demonstrated increased collagen deposition and ECM remodelling in mPVAT from obese male compared with obese female mice. Assessment of vascular function in mesenteric arteries -/+ PVAT revealed that in obesity, mPVAT impaired endothelium-mediated vasodilation in male but not female mice. Ovariectomy of female mice prior to HFD administration did not alter ECM transcript expression or collagen deposition in mPVAT compared to sham-operated female mice. Conclusions: Obesity induces sex-specific molecular remodelling in mPVAT, with male mice exhibiting unique upregulation of ECM pathways and increased collagen deposition compared to females. Moreover, the relative protection of female mice from obesity-induced mPVAT dysregulation is not mediated by ovarian hormones. These data highlight a potential sex-specific mechanistic link between mPVAT and mesenteric artery dysfunction in obesity, and provides crucial insights for future development of treatment strategies that consider the unique cardiovascular risks in men and women. [ABSTRACT FROM AUTHOR]

Aims Endothelial cell (EC) dysfunction drives the initiation and pathogenesis of pulmonary arterial hypertension (PAH). We aimed to characterize EC dynamics in PAH at single-cell resolution. Methods and results We carried out single-cell RNA sequencing (scRNA-seq) of lung ECs isolated from an EC lineage-tracing mouse model in Control and SU5416/hypoxia-induced PAH conditions. EC populations corresponding to distinct lung vessel types, including two discrete capillary populations, were identified in both Control and PAH mice. Differential gene expression analysis revealed global PAH-induced EC changes that were confirmed by bulk RNA-seq. This included upregulation of the major histocompatibility complex class II pathway, supporting a role for ECs in the inflammatory response in PAH. We also identified a PAH response specific to the second capillary EC population including upregulation of genes involved in cell death, cell motility, and angiogenesis. Interestingly, four genes with genetic variants associated with PAH were dysregulated in mouse ECs in PAH. To compare relevance across PAH models and species, we performed a detailed analysis of EC heterogeneity and response to PAH in rats and humans through whole-lung PAH scRNA-seq datasets, revealing that 51% of up-regulated mouse genes were also up-regulated in rat or human PAH. We identified promising new candidates to target endothelial dysfunction including CD74, the knockdown of which regulates EC proliferation and barrier integrity in vitro. Finally, with an in silico cell ordering approach, we identified zonation-dependent changes across the arteriovenous axis in mouse PAH and showed upregulation of the Serine/threonine-protein kinase Sgk1 at the junction between the macro- and microvasculature. Conclusion This study uncovers PAH-induced EC transcriptomic changes at a high resolution, revealing novel targets for potential therapeutic candidate development. [ABSTRACT FROM AUTHOR]

Author(s): Victoria K. Snowdon 1, Neil J. Lachlan 1, Anna M. Hoy 1, Patrick W. F. Hadoke 2, Scott I. Semple 2,3, Dilip Patel 4, Will Mungall 5, Timothy J. [...], Background Chronic liver scarring from any cause leads to cirrhosis, portal hypertension, and a progressive decline in renal blood flow and renal function. Extreme renal vasoconstriction characterizes hepatorenal syndrome, a functional and potentially reversible form of acute kidney injury in patients with advanced cirrhosis, but current therapy with systemic vasoconstrictors is ineffective in a substantial proportion of patients and is limited by ischemic adverse events. Serelaxin (recombinant human relaxin-2) is a peptide molecule with anti-fibrotic and vasoprotective properties that binds to relaxin family peptide receptor-1 (RXFP1) and has been shown to increase renal perfusion in healthy human volunteers. We hypothesized that serelaxin could ameliorate renal vasoconstriction and renal dysfunction in patients with cirrhosis and portal hypertension. Methods and findings To establish preclinical proof of concept, we developed two independent rat models of cirrhosis that were characterized by progressive reduction in renal blood flow and glomerular filtration rate and showed evidence of renal endothelial dysfunction. We then set out to further explore and validate our hypothesis in a phase 2 randomized open-label parallel-group study in male and female patients with alcohol-related cirrhosis and portal hypertension. Forty patients were randomized 1:1 to treatment with serelaxin intravenous (i.v.) infusion (for 60 min at 80 [mu]g/kg/d and then 60 min at 30 [mu]g/kg/d) or terlipressin (single 2-mg i.v. bolus), and the regional hemodynamic effects were quantified by phase contrast magnetic resonance angiography at baseline and after 120 min. The primary endpoint was the change from baseline in total renal artery blood flow. Therapeutic targeting of renal vasoconstriction with serelaxin in the rat models increased kidney perfusion, oxygenation, and function through reduction in renal vascular resistance, reversal of endothelial dysfunction, and increased activation of the AKT/eNOS/NO signaling pathway in the kidney. In the randomized clinical study, infusion of serelaxin for 120 min increased total renal arterial blood flow by 65% (95% CI 40%, 95%; p < 0.001) from baseline. Administration of serelaxin was safe and well tolerated, with no detrimental effect on systemic blood pressure or hepatic perfusion. The clinical study&apos;s main limitations were the relatively small sample size and stable, well-compensated population. Conclusions Our mechanistic findings in rat models and exploratory study in human cirrhosis suggest the therapeutic potential of selective renal vasodilation using serelaxin as a new treatment for renal dysfunction in cirrhosis, although further validation in patients with more advanced cirrhosis and renal dysfunction is required. Trial registration ClinicalTrials.gov NCT01640964

Aims Cardiovascular thrombosis is responsible a quarter of deaths annually worldwide. Current imaging methods for cardiovascular thrombosis focus on anatomical identification of thrombus but cannot determine thrombus age or activity. Molecular imaging techniques hold promise for identification and quantification of thrombosis in vivo. Our objective was to assess a novel optical and positron-emitting probe targeting Factor XIIIa (ENC2015) as biomarker of active thrombus formation. Methods and results Optical and positron-emitting ENC2015 probes were assessed ex vivo using blood drawn from human volunteers and passed through perfusion chambers containing denuded porcine aorta as a model of arterial injury. Specificity of ENC2015 was established with co-infusion of a factor XIIIa inhibitor. In vivo 18F-ENC2015 biodistribution, kinetics, radiometabolism, and thrombus binding were characterized in rats. Both Cy5 and fluorine-18 labelled ENC2015 rapidly and specifically bound to thrombi. Thrombus uptake was inhibited by a factor XIIIa inhibitor. 18F-ENC2015 remained unmetabolized over 8 h when incubated in ex vivo human blood. In vivo , 42% of parent radiotracer remained in blood 60 min post-administration. Biodistribution studies demonstrated rapid clearance from tissues with elimination via the urinary system. In vivo, 18 F-ENC2015 uptake was markedly increased in the thrombosed carotid artery compared to the contralateral patent artery (mean standard uptake value ratio of 2.40 vs. 0.74, P  < 0.0001). Conclusion  ENC2015 rapidly and selectively binds to acute thrombus in both an ex vivo human translational model and an in vivo rodent model of arterial thrombosis. This probe holds promise for the non-invasive identification of thrombus formation in cardiovascular disease. [ABSTRACT FROM AUTHOR]