Hypertensive Arteries Research Articles

Personalized Food Avoidance Dietary Approach for Psoriasis and Hypertension: A Case Study and Pilot Trial

Background: The comorbidity, coheritability and common immune pathways of the inflammatory ‘chronic’ (non-communicable) diseases, suggest a shared aetiopathogenic mechanism, with phenotypic localization dependent on genetic predisposition, for example, the arteries in hypertension and the skin in psoriasis. Lifelong observation of psoriasis suggests genetically predisposed toxicity of amphiphilic fats, flavor enhancers, and nonsugar sweeteners. Aim: To conduct trials of personalized dietary intervention to abate the phenotypic expression of psoriasis and hypertension. Materials and Methods: The interventional case study of psoriasis was conducted by means of repetitive dietary challenge and avoidance testing. We then conducted an open trial of personalized nutrition on nine consenting recruits with uncomplicated essential hypertension. They were counseled on which foods to avoid or to take based on the experience gained in psoriasis. Study participants with ‘GOOD’ or ‘FAIR/POOR’ dietary compliance were compared with regard to blood pressure (BP) control, antihypertensive drug treatment requirement (ADTR), and anthropometry. Results: Data from four FAIR/POOR diet compliers and three GOOD compliers, as at 29 weeks of dietary intervention, showed mean systolic home BP values of 128.1 (±6.74) mmHg and 122.3 (±2.03) mmHg, respectively; the mean systolic automated office BP values were 139.8 (±8.80) mmHg and 108.3 (±5.55) mmHg, respectively; as at 39 weeks of dietary intervention, the mean ADTR scores were 4.2 (±2.12) and 1.03 (±0.57), respectively. Using data at baseline and from all available timepoints after dietary intervention, two-way ANOVA confirmed highly significant improvement of BP control (P < 0.0001) and reduction of ADTR score (P = 0.0008) in GOOD compliers. GOOD compliers exhibited significantly more reductions in BMI, abdominal circumference, and triceps skinfold thickness than FAIR/POOR compliers (two-way ANOVA and linear regression: P < 0.05). Conclusion: These results support the case for adverse dietary exposure avoidance to abate the phenotypic expression of chronic disease.

LncRNA-536 and RNA Binding Protein RBM25 Interactions in Pulmonary Arterial Hypertension.

Hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) is one of the essential features of the maladaptive inward remodeling of the pulmonary arteries in pulmonary arterial hypertension (PAH). In this study, we define the mechanistic association between long-noncoding RNA: ENST00000495536 (Lnc-536) and anti-proliferative HOXB13 in mediating smooth muscle hyperplasia. Antisense oligonucleotide-based GapmeRs or plasmid overexpressing lnc-536 were used to evaluate the role of lnc-536 in mediating hyperproliferation of PDGF-treated or idiopathic PAH (IPAH) PASMCs. Further, we pulled down lnc536 to identify the proteins directly interacting with lnc536. The in-vivo role of lnc-536 was determined in Sugen-hypoxia and HIV-transgenic pulmonary hypertensive rats. Increased levels of lnc-536 in PDGF-treated or IPAH PASMCs promote hyperproliferative phenotype by downregulating the HOXB13 expression. Knockdown of lnc-536 in-vivo prevented increased RVSP, Fulton Index, and pulmonary vascular remodeling in Sugen-Hypoxia rats. The lncRNA-536 pull-down assay demonstrated the interactions of RNA binding protein: RBM25 with SFPQ, a transcriptional regulator that has a binding motif on HOXB13 exon Further, The RNA-IP experiment using the SFPQ antibody showed direct interaction of RBM25 with SFPQ and knockdown of RBM25 resulted in increased interactions of SFPQ and HOXB13 mRNA while attenuating PASMC proliferation. Finally, we examined the role of lnc-536 and HOXB13 axis in the PASMCs exposed to the dual hit of HIV and a stimulant: cocaine as well. lnc-536 acts as a decoy for RBM25, which in turn sequesters SFPQ, leading to the decrease in HOXB13 expression and hyperproliferation of smooth muscle cells associated with PAH development.

Zonation, ligand and dose dependence of S1PR1 signalling in blood and lymphatic vasculature.

Circulating levels of sphingosine 1-phosphate (S1P), an HDL-associated ligand for endothelial cell (EC) protective S1P receptor-1 (S1PR1), are reduced in disease states associated with endothelial dysfunction. Yet as S1PR1 has high affinity for S1P and can be activated by ligand-independent mechanisms and EC-autonomous S1P production, it is unclear if relative reductions in circulating S1P impact endothelial function. It is also unclear how EC S1PR1 insufficiency, whether induced by ligand deficiency or by S1PR1-directed immunosuppressive therapy, affects different vascular subsets. We here fine-map the zonation of S1PR1 signalling in the murine blood and lymphatic vasculature, superimpose cell type-specific and relative deficiencies in S1P production to define ligand source- and dose-dependence, and correlate receptor engagement to essential functions. In naïve blood vessels, despite broad expression, EC S1PR1 engagement was restricted to resistance-size arteries, lung capillaries and high-endothelial venules (HEV). Similar zonation was observed for albumin extravasation in EC S1PR1 deficient mice, and brain extravasation was reproduced with arterial EC-selective S1pr1 deletion. In lymphatic EC, S1PR1 engagement was high in collecting vessels and lymph nodes and low in terminal capillaries that drain tissue fluids. While EC S1P production sustained S1PR1 signaling in lymphatics and HEV, hematopoietic cells provided ∼90% of plasma S1P and sustained signaling in resistance arteries and lung capillaries. S1PR1 signaling and endothelial function were both surprisingly sensitive to reductions in plasma S1P with apparent saturation around 50% of normal levels. S1PR1 engagement did not depend on sex or age, but modestly increased in arteries in hypertension and diabetes. Sphingosine kinase (Sphk)-2 deficiency also increased S1PR1 engagement selectively in arteries, which could be attributed to Sphk1-dependent S1P release from perivascular macrophages. This study highlights vessel subtype-specific S1PR1 functions and mechanisms of engagement and supports the relevance of S1P as circulating biomarker for endothelial function.

Optimization of pulmonary artery mechanical testing

Pulmonary arterial hypertension (PAH) is an incurable disease with mortality within 3 years in 28-55% of high-risk patients. The progression of PAH has been known to be associated with increased vascular stiffness and vascular remodeling. Recent studies have suggested that increased stiffness may in fact be a driver for some of the metabolic abnormalities observed during PAH. To gain more insights into this relationship, we need to quantify the differences in mechanical properties of healthy and hypertensive pulmonary arteries. The stress-strain relationship is the gold standard for the ex-vivo stiffness measurement of arteries. This is obtained by obtaining force vs. distension data by tensile testing and using sample dimensions, i.e. length, lumen diameter, and wall thickness, to calculate engineering stress and strain. While this approach is well-optimized for large muscular arteries, it has not been used to test pulmonary arteries as their thin walls and low basal tone make it challenging to make precise measurements of sample wall thickness and lumen diameter. Thus, the goals of this study were to: 1) establish a reliable protocol for rat pulmonary artery tensile testing and 2) quantify the differences in stiffness between hypertensive and healthy pulmonary arteries. First, a methodology to improve the fidelity of determining the lumen diameter and wall thickness was developed. Using this approach, we observed that the modulus was negatively correlated with the length of the vessel segment tested. This suggests that vessel length should be standardized to perform reliable comparisons between groups. Next, we performed tensile tensing on both control and hypertensive pulmonary arteries, after standardizing vessel segment lengths. We initially modeled this tensile testing data using a one-term exponential equation and we observed that intact hypertensive arteries were ~2.7 times stiffer than control arteries at low strain (strain = 0.8). Whereas at high strain (strain = 2.8) intact and decellularized hypertensive arteries were 20 and 29 times stiffer than control arteries respectively. To better capture the viscoelastic properties of both, the cellular and ECM components of the vessels we also fit the tensile testing data using a two-term exponential equation. Using this two-term exponential model, we observed that hypertensive vessels were 2.2 times stiffer than the controls at normal hoop stress (20 kPa), and at the hypertensive hoop stress (66 kPa) the diseased vessels showed less variability in stiffness as compared to the controls. These findings and the methods developed in this study will be helpful in conducting and analyzing experiments to investigate the relationship between changes in biomechanical signals and the progression of PAH. R01HL151530 (KS), R01HL126514 (LS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Multi-scaled temporal modeling of cardiovascular disease progression: An illustration of proximal arteries in pulmonary hypertension

The progression of cardiovascular disease is intricately influenced by a complex interplay between physiological pathways, biochemical processes, and physical mechanisms. This study aimed to develop an in-silico physics-based approach to comprehensively model the multifaceted vascular pathophysiological adaptations. This approach focused on capturing the progression of proximal pulmonary arterial hypertension, which is significantly associated with the irreversible degradation of arterial walls and compensatory stress-induced growth and remodeling. This study incorporated critical characteristics related to the distinct time scales for the deformation, thus reflecting the impact of mean pressure on artery growth and tissue damage. The in-silico simulation of the progression of pulmonary hypertension was realized based on computational code combined with the finite element method (FEM) for the simulation of disease progression. The parametric studies further explored the consequences of these irreversible processes. This computational modeling approach may advance our understanding of pulmonary hypertension and its progression.

RNA ve protein seviyelerinde temel biyobelirteçleri belirlemek için pulmoner arteriyel hipertansiyonun in silico analizi

Pulmonary arterial hypertension (PAH) is a chronic cardiopulmonary disorder marked by a raised hypertension in the pulmonary arteries. There is no remedy for PAH, existing medications can help reduce the disease’s progression. This research aimed to investigate potential protein and RNA biomarkers of PAH by bioinformatic analysis. Two PAH datasets accessed from the publicly available Gene Expression Omnibus (GEO) database were used to discover differentially expressed genes (DEGs). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses for common DEGs were conducted by the DAVID tool. Cytoscape was used to create the protein-protein interaction (PPI) and pick the top 10 hub genes. The transcription factors (TFs) and microRNAs (miRNAs) that target DEGs and hub genes were investigated using the JASPAR database. Potential therapeutics that target the top hub genes have been discovered. Ten hub genes were discovered to be linked to the pathogenesis of PAH (CCL5, TLR4, TLR1, SPP1, CYBB, HGF, IGF1, SELL, CD163, and POSTN). “Positive regulation of tumor necrosis factor biosynthetic process” and a “toll-like receptor signaling pathway” are the most enriched GO term and KEGG pathway, respectively. “hsa-mir-26b-5p, hsa-mir-146a-5p, hsa-mir-335-5p” and FOXC1, YY1, GATA2 are the top TFs targeting hub genes. 21 drugs targeting ten hub genes have been discovered. Our results would help to discover the pathogenesis of PAH and hub genes, miRNAs and 10 TFs that might serve as potential therapeutic targets at protein and RNA levels for PAH patients.

Gender differences in the antihypertensive effect after radiofrequency denervation of the renal arteries in resistant arterial hypertension

Objective: evaluation of gender differences in the antihypertensive effect after denervation of the renal arteries based on the results of office and daily measurements of blood pressure in resistant arterial hypertension in a 3-year follow-up.Materials and methods: the study involved 80 patients with resistant arterial hypertension (RAH); Patients were divided by stratification randomization into the interventional treatment group, who continue to receive antihypertensive therapy (AHT) (RDN group) and the MT group (patients on drug therapy only. The study groups were comparable in terms of gender, age, duration of hypertension, the number of antihypertensive drugs taken, the presence of For 12 months, a comparative study was conducted between groups, further analysis of the effectiveness of surgical treatment of RDN PA was carried out at control points of 24 and 36 months, in which laboratory and instrumental examinations were performed.Results: according to the office measurement of blood pressure within the RDN and MT study groups, both in men and women, it turned out to be similar. After 12 months of observation between the comparison groups, the women of the group showed a statistically significant negative dynamics of the office SBP (p<0.01) and office DBP (p<0.05) parameters. According to the analysis of average daily, average daily, average night SBP indicators, after 12 months in the RDN group, a decrease was observed in all main parameters (p<0.001). It is worth paying attention to the fact that in the MT group, among the average daily, average daily, average night ABPM indicators after 12 months, no statistically significant changes were detected. When conducting a gender analysis of ABPM indicators using the Friedman test and correcting the p value for multiple comparisons at visits of 24 and 36 months, a statistically significant decrease in the main average daily indicators in women was demonstrated, while in men such changes were not established.Conclusions: the data obtained indicate a more pronounced antihypertensive effect after radiofrequency denervation of the renal arteries in resistant arterial hypertension in women.

MULTIPLE RENAL ARTERIES AS A RISK FACTOR FOR SEVERE HYPERTENSION IN YOUNG ADULTS?

Objective: The significance of multiple renal arteries (MRAs) in arterial hypertension (AH) is not fully understood. Lower perfusion pressure due to longer length and narrower caliber of MRAs could cause segmental hyperreninemia sufficient to result in renin-dependent systemic hypertension. Sympathetic renal nerve activity might be affected by hyperreninema as well. The aim of the study was to examine the characteristics of young adult hypertensives in relation to the existence of MRAs that were diagnosed during evaluation for secondary arterial hypertension. Design and method: 32 patients underwent routine evaluation for secondary hypertension and target organ damage. Patients were divided into two groups, one with MRAs and the other without MRAs. Data were presented as mean +standard deviation and compared by the Indipendent-Sample t-test. Results: The mean age was 38 years, and 13 patients were diagnosed with MRAs. There were more men in the MRAs group, otherwise, there were no significant differences in baseline characteristics between the groups (BMI, smoking, family history). None of them were diagnosed with secondary endocrine hypertension or renal artery stenosis. MRAs group showed significantly higher values of office SBP/DBP (p < 0,012) and 24-hour SBP/DBP (p < 0,001), and nonsignificantly higher values of heart rate. Although nonsignificant, direct renin concentrations were slightly higher in the MRAs group, while insulin levels were higher in the non-MRAs group. Dyslipidemia was diagnosed in most patients, without significant differences between groups. Electrocardiographic and echocardiographic changes suggesting hypertensive heart remodeling were found in 55% of patients in MRAs compared to 32% in non-MRAs, there were no significant differences in NTproBNP levels. A nonsignificant reduction in glomerular filtration rate was noticed in the MRAs group, while there were no significant differences in 24-hour albuminuria (p 0,308; p 0,614). Conclusions: The significance of MRAs in arterial hypertension is a matter of debate. In our study of young patients with arterial hypertension and MRAs, we observed features of more severe hypertension with already existing hypertensive target organ damages. Proper medical treatment with antihypertensive agents is crucial. Future studies will answer the question about interventional therapeutic procedures’ role in preventing cardiovascular complications.

RSK2 deletion alters vascular function and hypertension in resistance mesenteric arteries of aged mice

Hypertension (HT), a condition that becomes increasingly prevalent with age, affects millions of Americans, and can lead to heart disease, stroke, and kidney failure. Pathophysiological mechanisms contributing to the increased peripheral vascular resistance associated with HT, include arterial remodeling, increased vascular contraction and reduced vasodilation. Vascular structural and functional changes of aging closely resemble the classical HT phenotype. Current antihypertensive medications are less than 50% effective at controlling blood pressure, highlighting the need for better therapeutic options. Recently, our group has demonstrated that p90 ribosomal s6 kinase (Rsk2) plays a significant physiological role in SM contractility. We have shown that young adult global Rsk2 KO mice had more dilated mesenteric arteries (MAs), with reduced vessel tone, stiffness and RLC20 phosphorylation, and significantly lower basal blood pressure compared to WT. However, it is unknown whether Rsk2 plays a functional role in age-related HT. We found that >24-month-old WT mice had a significantly higher mortality rate compared to aged-match Rsk2 KO. Baseline Systolic blood pressure (SBP) was significantly lower in KOs compared to WT. L-NAME elevated SBP in WT but not in KO mice. There were no differences in echo parameters in WT and Rsk2 KO aged mice. Histology of 3rd and 4th order WT and Rsk2 KO MA cross-sections revealed no differences in lumen diameter, wall, thickness, or ratio of wall area to total area in aged mice. Thus, Rsk2 deletion did not alter vascular remodeling in resistance arteries of aged mice. Pressure myography studies assessed vascular reactivity and arterial stiffness in MAs isolated from Rsk2 KO and WT mice. Myogenic tone was significantly lower in Rsk2 KO 3rd and 4th order resistance arteries. Vascular stiffness, in aged WT and aged Rsk2 KO mice did not differ but was significantly increased when compared to young WT mice. Resistance MAs (<200 μm) from young and aged WT mice were examined for Ca2+ signals, and relaxation to spermine NONOate after 88 wk of age. Arteries from aged mice experienced an attenuated vasodilatory response to the NO donor at 1 and 3 μM when compared to arteries from young mice. Spontaneous Ca2+ frequency was significantly increased in aged mice compared to young mice. Ca2+ frequency in young mice was attenuated by the RSK inhibitor LJH685 (5 μM), but unchanged in aged mice. The mean Ca2+ amplitude in MAs from aged mice was significantly upregulated when compared to young mice, and significantly attenuated by LJH685 in both young and aged arteries. Our data suggest that in the absence of Rsk2, vessel remodeling and changes in BP are dissociated in aged mice. Furthermore, we have shown that Rsk2 serves as a mediator of downstream signaling elements that alter vascular function in aged mice by decreasing NO sensitivity and enhancing [Ca2+]i resulting in an increase in vascular tone that contributes to HT. NIH grant for AVS: HL147555; Research Supplements for RJA. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Pulmonary artery blood flow dynamics in chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension is caused by incomplete resolution and organization of thrombi. Blood flow dynamics are involved in thrombus formation; however, only a few studies have reported on pulmonary artery blood flow dynamics in patients with chronic thromboembolic pulmonary hypertension. Furthermore, the effects of treatment interventions on pulmonary artery blood flow dynamics are not fully understood. The aim of the study was to evaluate pulmonary artery blood flow dynamics in patients with chronic thromboembolic pulmonary hypertension before and after pulmonary endarterectomy and balloon pulmonary angioplasty, using computational fluid dynamics. We analyzed patient-specific pulmonary artery models of 10 patients with chronic thromboembolic pulmonary hypertension and three controls using computational fluid dynamics. In patients with chronic thromboembolic pulmonary hypertension, flow velocity and wall shear stress in the pulmonary arteries were significantly decreased, and the oscillatory shear index and blood stagnation volume were significantly increased than in controls. Pulmonary endarterectomy induced redistribution of pulmonary blood flow and improved blood flow dynamics in the pulmonary artery. Balloon pulmonary angioplasty improved pulmonary blood flow disturbance, decreased blood flow stagnation, and increased wall shear stress, leading to vasodilatation of the distal portion of the pulmonary artery following balloon pulmonary angioplasty treatment.

A modified primary culture method of rat pulmonary vein smooth muscle cells

BackgroundAlthough the pressure of pulmonary vein increases before pulmonary artery in pulmonary hypertension due to left heart disease (PH-LHD), only a few studies have assessed pulmonary vein smooth muscle cells (PVSMCs) because of the lack of a simple and feasible isolation method.MethodsIn this study, we introduced a simple method to obtain PVSMCs. Primary pulmonary veins were removed by puncture needle cannula guidance. Then, PVSMCs were cultured by the tissue explant method and purified by the differential adhesion method. The cells were characterized by hematoxylin-eosin (HE) staining, immunohistochemistry, western blotting, and immunofluorescence to observe the morphology and verify the expression of alpha-smooth muscle actin (α-SMA).ResultsThe HE staining results showed that the pulmonary vein media was thinner than the pulmonary artery, the intima and adventitia of the pulmonary vein were removed by this method, and the obtained cells with good activity exhibited morphological characteristics of smooth muscle cells. In addition, higher α-SMA expression was observed in the cells obtained by our isolation method than in the traditional method.ConclusionThis study established a simple and feasible method to isolate and culture PVSMCs that might facilitate the cytological experiments for PH-LHD.

Stenosis of the trunk of the left coronary artery in idiopathic pulmonary hypertension. Case report

The manuscript presents a clinical case of treatment of a patient with idiopathic pulmonary hypertension and a rare complication left main coronary artery stenosis caused due to compression by the dilated pulmonary artery. This complication was clinically manifested by chest pain. The patient underwent percutaneous coronary angioplasty with stenting of the left main coronary artery and subsequent prescription of combined PAH-specific therapy. During the late follow-up examination in addition to clinical improvement and the absence of pain, 6-minute walking test distance increase, positive dynamics of echocardiography, right heart catheterization, as well as the laboratory marker of heart failure NT-proBNP were noted.

Salt Restriction and Angiotensin-Converting Enzyme Inhibitor Improve the Responsiveness of the Small Artery in Salt-Sensitive Hypertension.

For salt-sensitive hypertension (SSH), salt restriction and angiotensin-converting enzyme (ACE) inhibitors are essential treatments, but their effect on the function of resistance arteries is unclear. Here, we present an intravital study to detect the effect of salt restriction and ACE inhibitors on the function of the mesenteric small artery (MSA) in SSH. Dahl salt-sensitive rats were randomized into the following groups: ACE inhibitor gavage, salt restriction, ACE inhibitor combined with salt restriction, and high-salt diet. After a 12-week intervention, the mesenteric vessels maintained their perfusion in vivo, and the changes in the diameter and blood perfusion of the MSAs to norepinephrine (NE) and acetylcholine (ACh) were detected. Switching from a high-salt diet to a low-salt diet (i.e., salt restriction) attenuated the vasoconstriction of the MSAs to NE and promoted the vasodilatation to ACh, while ACE inhibitor improved the vasodilatation more obviously. Pathologically, changes in local ACE, AT1R, and eNOS expression were involved in these processes induced by a high-salt diet. Our study suggests that salt restriction and ACE inhibitor treatment improve high salt intake-induced MSA dysfunction in SSH, and salt restriction is a feasible and effective treatment. Our findings may provide a scientific basis for the treatment of hypertension.

Quercetin decreases cardiac hypertrophic mediators and maladaptive coronary arterial remodeling in renovascular hypertensive rats without improving cardiac function.

Oxidative stress and MMP activity are found in the hearts and arteries in hypertension and contribute to the resulting hypertrophy and dysfunction. Quercetin is a flavonoid that reduces MMP-2 activity and ameliorates hypertrophic vascular remodeling of hypertension. The hypothesis is that treatment of hypertensive rats with quercetin ameliorates coronary maladaptive remodeling and decreases hypertrophic cardiac dysfunction by decreasing oxidative stress and MMP activity. Male Sprague-Dawley two-kidney, one-clip (2K1C) and Sham rats were treated with quercetin (10mg/kg/day) or its vehicle for 8weeks by gavage. Rats were analyzed at 10weeks of hypertension. Systolic blood pressure (SBP) was examined by tail-cuff plethysmography. Cardiac left ventricles were used to determine MMP activity by in situ zymography and oxidative stress by dihydroethidium. Immunofluorescence was performed to detect transforming growth factor (TGF)-β and nuclear factor kappa B (NFkB). Morphological analyses of heart and coronary arteries were done by H&E and picrosirius red, and cardiac function was measured by Langendorff. SBP was increased in 2K1C rats, and quercetin did not reduce it. However, quercetin decreased both oxidative stress and TGF-β in the left ventricles of 2K1C rats. Quercetin also decreased the accentuated MMP activity in left ventricles and coronary arteries of 2K1C rats. Quercetin ameliorated hypertension-induced coronary arterial hypertrophic remodeling, although it did not reduce cardiac hypertrophic remodeling and dysfunction. Quercetin decreases cardiac oxidative stress and TGF-β and MMP activity in addition to improving coronary remodeling, yet does not ameliorate cardiac dysfunction in 2K1C rats.

S-Nitrosylation-Mediated Reduction of CaV1.2 Surface Expression and Open Probability Underlies Attenuated Vasoconstriction Induced by Nitric Oxide.

L-type CaV1.2 calcium channel, the primary gateway for Ca2+ influx in smooth muscles, is widely regulated by multiple posttranslational modifications, such as protein kinase-mediated phosphorylation and nitric oxide-induced S-nitrosylation. However, the effect of S-nitrosylation on CaV1.2 channel function and its role in arterial contractility are not well understood. Electrophysiological recordings, Ca2+ and confocal imaging, and biochemical assays were used to functionally characterize S-nitrosylated CaV1.2 channels in vitro, while pressure myography and tail-cuff blood pressure measurement were conducted to evaluate the physiological effects of CaV1.2 S-nitrosylation ex vivo and in vivo. S-nitrosylation significantly reduced the CaV1.2 current density by promoting lysosomal degradation that leads to decreased levels of total and surface CaV1.2 channel proteins in a CaVβ-independent manner and reducing the open probability of CaV1.2 channel. Mechanistically, the Cys1180 and Cys1280 residues within CaV1.2 channel have been determined as the molecular targets for S-nitrosylation as substitution of either Cys1180 or Cys1280 for serine resulted in substantial reduction of S-nitrosylation levels. Of note, CaV1.2 S-nitrosylation levels were significantly reduced in arteries isolated from both spontaneously hypertensive rats and patients with pulmonary hypertension. Moreover, mouse resistance arteries incubated with S-nitrosocysteine displayed much lower contractility and spontaneously hypertensive rats injected with S-nitrosocysteine also showed significantly reduced blood pressure, suggesting that reduced S-nitrosylation contributes to the upregulation of CaV1.2 channel activity in hypertensive arteries. This study provides strong evidence that S-nitrosylation-mediated downregulation of CaV1.2 channels is via 2 distinctive mechanisms and the findings offer potential pathways for therapeutic inventions in hypertension.

Total Occlusion of the Left Main Coronary Artery in Pulmonary Arterial Hypertension

Total Occlusion of the Left Main Coronary Artery in Pulmonary Arterial Hypertension

A Mathematical Model of Maladaptive Inward Eutrophic Remodeling of Muscular Arteries in Hypertension.

We propose a relatively simple two-dimensional mathematical model for maladaptive inward remodeling of resistive arteries in hypertension in terms of vascular solid mechanics. The main premises are: (i) maladaptive inward remodeling manifests as a reduced increase in the arterial mass compared to the case of adaptive remodeling under equivalent hypertensive pressures and (ii) the pressure-induced circumferential stress in the arterial wall is restored to its basal target value as happens in the case of adaptive remodeling. The rationale for these assumptions is the experimental findings that elevated tone in association with sustained hypertensive pressure down-regulate the normal differentiation of vascular smooth muscle cells from contractile to synthetic phenotype and the data for the calculated hoop stress before and after completion of remodeling. Results from illustrative simulations show that as the hypertensive pressure increases, remodeling causes a nonmonotonic variation of arterial mass, a decrease in inner arterial diameter, and an increase in wall thickness. These findings and the model prediction that inward eutrophic remodeling is preceded by inward hypertrophic remodeling are supported by published observations. Limitations and perspectives for refining the mathematical model are discussed.

Effects of 3-methyladenine, an autophagy inhibitor, on the elevated blood pressure and arterial dysfunction of angiotensin II-induced hypertensive mice

Autophagy is an intracellular degradation system that disassembles cytoplasmic components through autophagosomes fused with lysosomes. Recently, it has been reported that autophagy is associated with cardiovascular diseases, including pulmonary hypertension, atherosclerosis, and myocardial ischemia. However, the involvement of autophagy in hypertension is not well understood. In the present study, we hypothesized that excessive autophagy contributes to the dysfunction of mesenteric arteries in angiotensin II (Ang II)-induced hypertensive mice. Treatment of an autophagy inhibitor, 3-methyladenine (3-MA), reduced the elevated blood pressure and wall thickness, and improved endothelium-dependent relaxation in mesenteric arteries of Ang II-treated mice. The expression levels of autophagy markers, beclin1 and LC3 II, were significantly increased by Ang II infusion, which was reduced by treatment of 3-MA. Furthermore, treatment of 3-MA induced vasodilation in the mesenteric resistance arteries pre-contracted with U46619 or phenylephrine, which was dependent on endothelium. Interestingly, nitric oxide production and phosphorylated endothelial nitric oxide synthase (p-eNOS) at S1177 in the mesenteric arteries of Ang II-treated mice were increased by treatment with 3-MA. In HUVECs, p-eNOS was reduced by Ang II, which was increased by treatment of 3-MA. 3-MA had direct vasodilatory effect on the pre-contracted mesenteric arteries. In cultured vascular smooth muscle cells (VSMCs), Ang II induced increase in beclin1 and LC3 II and decrease in p62, which was reversed by treatment of 3-MA. These results suggest that autophagy inhibition exerts beneficial effects on the dysfunction of mesenteric arteries in hypertension.

H2S releasing sodium sulfide protects against pulmonary hypertension by improving vascular responses in monocrotaline-induced pulmonary hypertension

Pulmonary arterial hypertension is caused by complex structural and functional changes in the endothelial and smooth muscle cells of pulmonary arteries. Hydrogen sulfide (H2S), a gasotransmitter, can potentially treat pulmonary hypertension by relaxing the pulmonary arteries and decreasing bronchial pressure. Although the role of H2S in systemic circulation has been examined, the H2S levels in pulmonary arteries, the role of H2S in endothelium-dependent vasorelaxation and the L-cysteine/H2S pathway in monocrotaline-induced pulmonary arterial hypertension have not been investigated. The rats were divided into control, monocrotaline, monocrotaline + Na2S, and Na2S groups. The right ventricular pressure and hypertrophy were evaluated. KCl, acetylcholine, and L-cysteine responses were obtained in the main pulmonary arteries by wire myograph. H2S levels were measured in pulmonary arteries and lungs by methylene blue assay. Right ventricular pressure and hypertrophy were increased by monocrotaline and ameliorated by Na2S. The KCl-induced contractions and relaxing responses to acetylcholine and L-cysteine in pulmonary arteries and H2S production in the lungs and pulmonary arteries were significantly attenuated in the monocrotaline group and augmented in the monocrotaline + Na2S group. These findings suggest that H2S levels were reduced, and L-cysteine-induced and endothelium-dependent relaxations were impaired in the pulmonary arteries in monocrotaline-induced pulmonary arterial hypertension. The H2S donor, Na2S, prevented endothelial dysfunction and increased pulmonary artery pressure and hypertrophy. Also, Na2S enhanced the L-cysteine-mediated responses and restored the diminished H2S levels in pulmonary arteries and the lungs. The treatments targeting H2S might be beneficial for promoting vascular alterations, i.e. endothelial dysfunction and impaired H2S-mediated relaxation in pulmonary arterial hypertension.

Computational analysis of the role of mechanosensitive Notch signaling in arterial adaptation to hypertension

Arteries grow and remodel in response to mechanical stimuli. Hypertension, for example, results in arterial wall thickening. Cell-cell Notch signaling between vascular smooth muscle cells (VSMCs) is known to be involved in this process, but the underlying mechanisms are still unclear. Here, we investigated whether Notch mechanosensitivity to strain may regulate arterial thickening in hypertension. We developed a multiscale computational framework by coupling a finite element model of arterial mechanics, including residual stress, to an agent-based model of mechanosensitive Notch signaling, to predict VSMC phenotypes as an indicator of growth and remodeling. Our simulations revealed that the sensitivity of Notch to strain at mean blood pressure may be a key mediator of arterial thickening in hypertensive arteries. Further simulations showed that loss of residual stress can have synergistic effects with hypertension, and that changes in the expression of Notch receptors, but not Jagged ligands, may be used to control arterial growth and remodeling and to intensify or counteract hypertensive thickening. Overall, we identify Notch mechanosensitivity as a potential mediator of vascular adaptation, and we present a computational framework that can facilitate the testing of new therapeutic and regenerative strategies.