BackgroundDespite the high prevalence of chronic venous insufficiency and varicose veins in the Western world, suitable pharmaceutical therapies for these venous diseases have not been explored to date. In this context, we recently reported that a chronic increase in venous wall stress or biomechanical stretch is sufficient to cause development of varicose veins through the activation of the transcription factor activator protein 1.Methods and ResultsWe investigated whether deleterious venous remodeling is suppressed by the pleiotropic effects of statins. In vitro, activator protein 1 activity was inhibited by two 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors, rosuvastatin and atorvastatin, in stretch‐stimulated human venous smooth muscle cells. Correspondingly, both statins inhibited venous smooth muscle cell proliferation as well as mRNA expression of the activator protein 1 target gene monocyte chemotactic protein 1 (MCP1). In isolated mouse veins exposed to an increased level of intraluminal pressure, statin treatment diminished proliferation of venous smooth muscle cells and protein abundance of MCP1 while suppressing the development of varicose veins in a corresponding animal model by almost 80%. Further analyses of human varicose vein samples from patients chronically treated with statins indicated a decrease in venous smooth muscle cell proliferation and MCP1 abundance compared with samples from untreated patients.ConclusionsOur findings imply that both atorvastatin and rosuvastatin effectively inhibit the development of varicose veins, at least partially, by interfering with wall stress–mediated activator protein 1 activity in venous smooth muscle cells. For the first time, this study reveals a potential pharmacological treatment option that may be suitable to prevent growth of varicose veins and to limit formation of recurrence after varicose vein surgery.

The regulator of G-protein signaling 5 (RGS5) acts as an inhibitor of Gαq/11 and Gαi/o activity in vascular smooth muscle cells (VSMCs), which regulate arterial tone and blood pressure. While RGS5 has been described as a crucial determinant regulating the VSMC responses during various vascular remodeling processes, its regulatory features in resting VSMCs and its impact on their phenotype are still under debate and were subject of this study. While Rgs5 shows a variable expression in mouse arteries, neither global nor SMC-specific genetic ablation of Rgs5 affected the baseline blood pressure yet elevated the phosphorylation level of the MAP kinase ERK1/2. Comparable results were obtained with 3D cultured resting VSMCs. In contrast, overexpression of RGS5 in 2D-cultured proliferating VSMCs promoted their resting state as evidenced by microarray-based expression profiling and attenuated the activity of Akt- and MAP kinase-related signaling cascades. Moreover, RGS5 overexpression attenuated ERK1/2 phosphorylation, VSMC proliferation, and migration, which was mimicked by selectively inhibiting Gαi/o but not Gαq/11 activity. Collectively, the heterogeneous expression of Rgs5 suggests arterial blood vessel type-specific functions in mouse VSMCs. This comprises inhibition of acute agonist-induced Gαq/11/calcium release as well as the support of a resting VSMC phenotype with low ERK1/2 activity by suppressing the activity of Gαi/o.

Due to gravity the venous vasculature in the lower extremities is exposed to elevated pressure levels which may be amplified by obesity or pregnancy. As a consequence, venules dilate and may be slowly transformed into varicose or spider veins. In fact, chronically elevated venous pressure was sufficient to cause the corkscrew-like enlargement of superficial veins in mice. We hypothesized that biomechanical activation of endothelial cells contributes to this process and investigated the inhibitory capacity of Magnolol in this context – a natural compound that features multiple properties counteracting cellular stress. While Magnolol did not influence endothelial capillary sprout formation, it interfered with proliferation, ERK1/2 activity, gelatinase activity as well as baseline production of reactive oxygen species in these cells or murine veins. The anti-oxidative and anti-proliferative capacity of Magnolol was mediated through stimulation of heme oxygenase-1 expression. Finally, local transdermal application of Magnolol attenuated pressure-mediated development of varicose/spider veins in mice and was accompanied by the absence of proliferating and MMP-2 positive endothelial cells. Collectively, our data identified Magnolol as a potent inhibitor of biomechanically evoked endothelial cell activity during pressure-mediated venous remodeling processes which contribute to the development of varicose and spider veins.

Concerns have been raised that regulatory programs to accelerate approval of cancer drugs in cancer may increase uncertainty about benefits and harms for survival and quality of life (QoL). We analyzed all pivotal clinical trials and all non‐pivotal randomized controlled trials (RCTs) for all cancer drugs approved for the first time by the FDA between 2000 and 2020. We report regulatory and trial characteristics. Effects on overall survival (OS), progression‐free survival and tumor response were summarized in meta‐analyses. Effects on QoL were qualitatively summarized. Between 2000 and 2020, the FDA approved 145 novel cancer drugs for 156 indications based on 190 clinical trials. Half of indications (49%) were approved without RCT evidence; 82% had a single clinical trial only. OS was primary endpoint in 14% of trials and QoL data were available from 25%. The median OS benefit was 2.55 months (IQR, 1.33‐4.28) with a mean hazard ratio for OS of 0.75 (95%CI, 0.72‐0.79, I2 = 42). Improvement for QoL was reported for 7 (4%) of 156 indications. Over time, priority review was used increasingly and the mean number of trials per indication decreased from 1.45 to 1.12. More trials reported results on QoL (19% in 2000‐2005; 41% in 2016‐2020). For 21 years, novel cancer drugs have typically been approved based on one single, often uncontrolled, clinical trial, measuring surrogate endpoints. This leaves cancer patients without solid evidence that novel drugs improve their survival or QoL and there is no indication towards improvement.

Chronic hypoxia increases the resistance of pulmonary arteries by stimulating their contraction and augmenting their coverage by smooth muscle cells (SMCs). While these responses require adjustment of the vascular SMC transcriptome, regulatory elements are not well defined in this context. Here, we explored the functional role of the transcription factor nuclear factor of activated T-cells 5 (NFAT5/TonEBP) in the hypoxic lung. Regulatory functions of NFAT5 were investigated in cultured artery SMCs and lungs from control (Nfat5fl/fl) and SMC-specific Nfat5-deficient (Nfat5(SMC)−/−) mice. Exposure to hypoxia promoted the expression of genes associated with metabolism and mitochondrial oxidative phosphorylation (OXPHOS) in Nfat5(SMC)−/− versus Nfat5fl/fl lungs. In vitro, hypoxia-exposed Nfat5-deficient pulmonary artery SMCs elevated the level of OXPHOS-related transcripts, mitochondrial respiration, and production of reactive oxygen species (ROS). Right ventricular functions were impaired while pulmonary right ventricular systolic pressure (RVSP) was amplified in hypoxia-exposed Nfat5(SMC)−/− versus Nfat5fl/fl mice. Scavenging of mitochondrial ROS normalized the raise in RVSP. Our findings suggest a critical role for NFAT5 as a suppressor of OXPHOS-associated gene expression, mitochondrial respiration, and ROS production in pulmonary artery SMCs that is vital to limit ROS-dependent arterial resistance in a hypoxic environment.

Objective The Stress Management and Resilience Training (SMART) program is an evidence-based intervention designed to build resilience in physicians in clinical practice. The objective of the current study was to assess the impact of the SMART program on academic physicians’ levels of resilience, subjective happiness, stress, and anxiety, and specifically during the implementation of a new hospital-wide Health Information System (HIS). Methods A total of 40 physicians in a tertiary care academic hospital were randomized (allocation ratio 1:1) to either the SMART intervention or the control condition. The SMART intervention consisted of one mandatory two-hour in-person workshop and an optional 24-week online program, designed to support the materials delivered in the workshop. Outcome measures were assessed using validated scales administered online at baseline and at 3-months and 6-months follow-up. Results After adjusting for baseline levels of each outcome, no statistically significant intervention effect was observed for resilience, subjective happiness, stress or anxiety at 3-months or 6-months follow-up. However, physicians in the intervention group demonstrated improvements in resilience, stress and anxiety at follow-up that were within the range of clinically relevant differences. Conclusions The findings of this exploratory study provide modest support that the SMART intervention may be beneficial for proactively addressing physician wellness during the implementation of a new HIS and that larger randomized trials are warranted. Trial registration NCT04384861.

Development of spider veins is caused by the remodeling of veins located in the upper dermis and promoted by risk factors such as obesity or pregnancy that chronically increase venous pressure. We have repeatedly shown that the pressure-induced increase in biomechanical wall stress is sufficient to evoke the formation of enlarged corkscrew-like superficial veins in mice. Subsequent experimental approaches revealed that interference with endothelial- and/or smooth muscle cell (SMC) activation counteracts this remodeling process. Here, we investigate whether the herbal agent glycyrrhetinic acid (GA) is a suitable candidate for that purpose given its anti-proliferative as well as anti-oxidative properties. While basic abilities of cultured venous SMCs such as migration and proliferation were not influenced by GA, it inhibited proliferation but not angiogenic sprouting of human venous endothelial cells (ECs). Further analyses of biomechanically stimulated ECs revealed that GA inhibits the DNA binding capacity of the mechanosensitive transcription factor activator protein-1 (AP-1) which, however, had only a minor impact on the endothelial transcriptome. Nevertheless, by decreasing gelatinase activity in ECs or mouse veins exposed to biomechanical stress, GA diminished a crucial cellular response in the context of venous remodeling. In line with the observed inhibitory effects, local transdermal application of GA attenuated pressure-mediated enlargement of veins in the mouse auricle. In summary, our data identifies GA as an inhibitor of EC proliferation, gelatinase activity and venous remodeling. It may thus have the capacity to attenuate spider vein formation and remodeling in humans.

Aim: The development of varicose veins is driven by risk factors that support the progression of venous hypertension, specifically, by chronically augmenting the circumferential tension of the venous wall. We have previously verified the relevance of this biomechanical stimulus for the activation of venous cells and the structural remodeling of the vein wall. Recent transcriptome analyses revealed an increase in the expression of the gene encoding prostaglandin-endoperoxide synthase 2 [cyclooxygenase 2 (COX-2)] in biomechanically stressed human vein endothelial cells. This observation prompted us to investigate the functional relevance of COX activity for the onset of pressure-induced venous remodeling. Methods: For the in vitro experiments, isolated mouse veins were exposed to elevated intraluminal pressure levels to study the markers of cellular activation. For the in vivo experiments, pressure-dependent varicose remodeling of veins was induced by ligation of an efferent vein in the mouse auricle. Diclofenac was applied to inhibit the activity of COX. Results: Short-term exposure to elevated pressure levels stimulated the abundance of activated matrixmetalloproteinase-2 (MMP-2) and mitogen activated protein kinase, ERK1/2, in isolated mouse veins, which was inhibited upon treatment with diclofenac. Transdermal application of diclofenac-containing phospholipid-micelles attenuated the corkscrew-like enlargement of veins and decreased the abundance of COX-2 and MMP-2 as well as cell proliferation in the venous wall.