bluuebunny/crossref_metadata_2025_split huggingface dataset:
6β‐Hydroxytestosterone, a Cytochrome P450 1B1 Metabolite of Testosterone, Contributes to Angiotensin II‐Induced Vascular Dysfunction in Male Mice
Authors: Pingili Ajeeth K , Jennings Brett L , Malik Kafait U 
Published: November 2023

Previously, we showed that 6β‐hydroxytestosterone (6β‐OHT), a cytochrome P450 1B1 (CYP1B1)‐derived metabolite of testosterone, contributes to the development of angiotensin II (Ang II)‐induced hypertension and renal dysfunction in male mice. Ang II‐induced hypertension is associated with vascular dysfunction. In the present study we determined the contribution of 6β‐OHT to Ang II action on vascular reactivity, endothelial dysfunction, hypertrophy and fibrosis. In Ang II‐treated Cyp1b1+/+ mice, responses of the thoracic aorta to phenylephrine (PE) and endothelin‐1 (ET‐1), media to lumen ratio were significantly increased compared to Ang II‐treated Cyp1b1−/− or castrated Cyp1b1+/+ mice. Treatment of the later two groups of mice with 6β‐OHT restored the effect of Ang II to increase responses of the thoracic aorta to phenylephrine (PE) and endothelin‐1 (ET‐1) and media to lumen ratio. Ang II infusion caused endothelial dysfunction, as indicated by decreased relaxation to acetylcholine (ACh) of the aorta from Cyp1b1+/+ but not Cyp1b1−/− or castrated Cyp1b1+/+ mice. 6β‐OHT did not alter Ang II‐induced endothelial dysfunction in Cyp1b1+/+ mice but resulted in endothelial dysfunction in Cyp1b1−/− or castrated Cyp1b1+/+ mice. Sodium nitroprusside(SNP)‐induced relaxation of the aorta was not altered in all the groups. Ang II infusion increased vascular fibrosis as indicated by increased α‐smooth muscle actin and collagen deposition, and reactive oxygen species production (ROS) as indicated by increased dihydroethidium (DHE) staining in Cyp1b1+/+ as compared to Cyp1b1−/− or castrated Cyp1b1+/+ mice. 6β‐OHT did not alter Ang II‐induced fibrosis or oxidative stress in Cyp1b1+/+ mice, however in Cyp1b1−/− or castrated mice it restored these effects of Ang II. These data suggest that 6β‐OHT contributes to the development of hypertension, most likely via increased ROS generation and vascular reactivity and hypertrophy, and that CYP1B1 could serve as a novel target for the development of agents that mitigate hypertension and associated pathogenesis.Support or Funding InformationThis work was supported by the National Institutes of Health and National Heart, Lung, and Blood Institute grants R01HL‐19134–40 and R01HL‐079109‐09
Hypertensive Pregnancy and the Relationship between Bone Mineral Density and Coronary Artery Calcification in Postmenopausal Women
Authors: Beckman John P , Camp Jon J , Lahr Brian D , Kearns Ann E , Miller Virginia M , Holmes David R 
Published: November 2023

ObjectivePreeclampsia, a hypertensive pregnancy disorder, increases the risk for cardiovascular disease including coronary artery calcification (CAC) as women age. Controversy exists regarding the relationship between bone mineral density (BMD) and CAC in menopausal women. This study was designed to determine and compare the relationship between BMD and CAC in postmenopausal women with defined histories of either normotensive or preeclamptic pregnancies.MethodsWomen who gave birth in Olmsted County, MN between 1976 and 1982 were identified from their medical record as having a preeclamptic pregnancy (PE, n=40) and were age/parity‐matched with women having normotensive pregnancies (NP, n=40). The study was approved by the IRB at Mayo Clinic and all participants gave written informed consent. Quantitative Computed Tomography was used to assess vertebral (T7‐9) BMD and CAC. Statistical analyses included linear regression with general estimating equation (GEE) to correct for within‐subject correlations.ResultsWomen averaged 35 years since the index pregnancy and were 60 years of age at the time of the study. CAC was significantly greater in women of the PE group (median (25th, 75th percentiles: 0 (0, 0.3) NP and 0 (0, 25) PE, P=0.026). There were no significant differences in cortical, trabecular or central BMD between PE and NP groups. However, there was a positive correlation between cortical BMD and CAC in the PE group (ρ=0.336, P=0.042) and a negative correlation between central BMD and CAC in the NP group (ρ=−0.392, P=0.017).ConclusionsAlthough CAC was greater in women with a history PE, BMD did not differ from women with a history of NP. Associations between cortical and central BMD with CAC differed by pregnancy history suggesting that there may be underlying differences in calcium metabolism associated with PE.Support or Funding InformationThis work was funded by grants from the NIH AG44170, AG034676, UL1 TR000135 and the Mayo Foundation.
The cardiovascular response to stroke in normal and hypertensive rats ‐ therapeutic or pathological?
Authors: McBryde Fiona , Thakkar Pratik , McGregor Ailsa , Paton Julian , Barrett Carolyn 
Published: November 2023

Over 80% of ischemic stroke patients show an abrupt increase in blood pressure (BP) in the hours and days following stroke; yet whether post‐stroke hypertension is beneficial or harmful remains controversial, and the underlying physiological basis is unclear. We propose that one reason for this uncertainty may be a difference in the cardiovascular response to stroke between normotensive subjects compared to those with pre‐existing hypertension. We hypothesized that hypertensive subjects may be less able to increase blood pressure after stroke.To investigate the dynamic cardiovascular response to stroke, Wistar (n=6, 393±34g) and spontaneously hypertensive (SH) rats (n=6, 377±29g) were placed under isofluorane anaesthesia (~3%), and instrumented with radio telemeters to record BP, ICP and brain tissue oxygen (p02) in the region of the future stroke penumbra. After a 1‐week recovery period, an ischemic stroke was induced via transient middle cerebral artery occlusion on Day 0, and recordings continued for 10 days after stroke.In both Wistar and SH rats, penumbra p02 decreased to less than half baseline levels during the 2‐hour occlusion period, but rapidly recovered to baseline levels within minutes of reperfusion. In Wistar rats, BP increased rapidly (+37±4 mmHg above baseline of 108±6 mmHg; p<0.01) within 48 hours of stroke, before returning to baseline levels by Day 4. The magnitude of the post‐stroke blood pressure increase was similar in SH rats, (+34±3 mmHg above a hypertensive baseline of 145±5 mmHg; p<0.01), however SH rats showed a more gradual return to baseline levels by Day 7 (p=0.0459). ICP reflects cerebral oedema, and was also increased after stroke in both groups, peaking at 16±5 mmHg (p=0.035) on Day 3 in Wistars, with a slightly but significantly smaller increase of 7±1 mmHg (p<0.01) in SH rats. Following re‐perfusion, penumbra p02 tended to remain at or above baseline levels for the full recording period in both rat groups.Contrary to our hypothesis, we found that ischemic stroke was associated with very similar patterns of elevated blood pressure and intracranial pressure, and steadily maintained penumbra tissue oxygen content, in both normotensive and hypertensive rats. That this post‐stroke surge in blood pressure persists even in subjects with pre‐existing hypertension, suggests that it may play a fundamental role in the defensive response to stroke. Future studies will determine the impact of preventing post‐stroke hypertension on the recovery from stroke, in particular the ability to maintain penumbra p02.Support or Funding InformationSupported by the Health Research Council of New Zealand, the EU IRSES scheme and Royal Society Newton Fellowship Alumni funding.
Interaction between angiotensin II (ANGII) receptor 1A (AT1AR) and adenosine receptors in the control of vascular function in mouse aorta and mesenteric arteries
Authors: Yadav Vishal R , Teng Bunyen , Mustafa Jamal S 
Published: November 2023

ANG II, a systemic vasoconstrictor and adenosine through its receptors (ARs) regulate vascular function. Recently, we have shown that acute ANG II stimulation enhanced A1AR dependent CYP4A mediated contraction in mesenteric arteries (MA). In addition, A2BAR dependent and partly KATP channel mediated relaxation was also reduced in MAs after ANG II stimulation (Yadav et al., 2015). Thus, suggesting a possible interaction between ARs and AT1R in the control of vascular function. The present study is designed to explore interaction between AR and AT1R. There are two types of AT1 receptors; AT1A is ubiquitously expressed where as AT1B expressed in aorta, resistance arteries, adrenal glands, pituitary, and hypothalamus. Considering ubiquitous tissue expression of AT1A receptors, we performed muscle tension studies in isolated MA and aorta from WT and AT1A KO mice. We used DMT wire myograph for MAs and organ bath for aortas to perform concentration response curves (CRCs) to various agonists. Our data showed a significant increase in contraction to A1AR agonist CCPA in MAs isolated from AT1A KO. The contraction observed at 10 and 100 nM of CCPA was 24.8 ± 13.7 (% PE) and 29.7 ± 14.8 in AT1A KO mice which was significantly higher compared to −4.8 ± 3.7 and 0.5 ± 3.2 observed in WT mice. NECA (non‐selective AR agonist) induced CRC was similar in WT and AT1A KO MAs. Pinacidil (KATP channel opener) and C21 (AT2 agonist) produced comparable CRCs in WT and AT1A KO MAs. In addition, comparable ACh, PE and KCl‐induced responses were present in MAs. In aorta, CRCs to CCPA, NECA, C21 and Pinacidil were comparable between WT and AT1A KO. However, PE‐induced contraction was significantly reduced in aorta of AT1A KO mice. ACh induced relaxation in aorta was 54.1 ± 4.4 (% PE) in AT1A KO compared to WT, 40.7±4.6 (p<0.05). Comparable contraction to ANG II in MAs suggests the involvement of AT1B receptors which needs further investigation. In conclusion, our data suggest an interaction between ARs and AT1A receptor in the control of vascular function.Support or Funding InformationSupported by HL 027339
Beneficial renal effect of multi‐glycoside of Tripterygium wilfordii Hook. F. in mice with salt‐sensitive hypertension
Authors: Wang Youping , Zhu Minjun , Wang Zhentao , Cui Lin , Liu Suxiao , Xie Shiyan , Shen Si , Xu Hui 
Published: November 2023

To clarify the effects of low‐dose of multi‐glycoside of Tripterygium wilfordii Hook. F. (GTW), an extract from a Chinese herb thunder god vine, on salt‐sensitive hypertension‐induced renal damage, we induced hypertension by uninephrectomy and deoxycorticosterone (DOCA)‐salt in mice with or without low‐dose of GTW treatment. DOCA‐salt treatment for 5 weeks increased mean arterial pressure (MAP) (P<0.01) and urinary albumin excretion (P<0.05), and also induced renal hypertrophy (P<0.01) compared with the control. Periodic acid‐Schiff and Masson's trichrome staining showed that DOCA‐salt treatment caused obvious glomerulosclrosis and tubulointerstitial injury in the renal cortex (P<0.05), and tubulointerstitial fibrosis compared with the control mice. Consistent with the results, renal collagen level determined using hydroxyproline assay was higher in DOCA‐salt‐treated mice compared with the control mice (P<0.05). Treatment with GTW at the low dose of 11.5 mg/kg/day by gavage had no effect on MAP and renal hypertrophy. However, it partially prevented renal morphological damage and reduced the increases in urinary albumin excretion and renal collagen (P<0.05). Our data showed that treatment with the low dose of GTW prevented renal damage induced by DOCA‐salt hypertension independently of their effects on blood pressure. The results indicate that low‐dose of GTW exhibits a protective effect on renal damage during salt‐sensitive hypertension. This work was supported in part by the National Natural Science Foundation of China (No. 81673734) and Henan Provincial Science and Technique Foundation for International Cooperation Program (No. 162102410048)Support or Funding InformationThis work was supported in part by the National Natural Science Foundation of China (No. 81673734) and Henan Provincial Science and Technique Foundation for International Cooperation Program (No. 162102410048)
Hypertension reduces expression of soluble guanylyl cyclase in the aorta via the Notch signaling pathway
Authors: Rippe Catarina , Zhu Baoyi , Krawczyk Katarzyna , Van Bavel Van Bavel Ed , Albinsson Sebastian , Sjölund Jonas , Bakker Erik N.T.P. , Swärd Karl 
Published: November 2023

Hypertension is a dominating risk factor for cardiovascular morbidity and mortality. Here, aiming to characterize the genomic response of the vascular wall to hypertension, we administered physiological saline (NaCl, n=6) or angiotensin II (AngII, n=6) to mice using osmotic mini‐pumps and performed gene expression analysis using microarrays. AngII treatment (3w) resulted in a robust increase in blood pressure (186±6 vs. 103±11 mmHg) and altered expression (at q=0) of 235 genes in the aorta, including GUCY1A3 and GUCY1B3 which encode subunits of soluble guanylyl cyclase (sGC), the major nitric oxide receptor in the vascular wall. Quantitative RT‐PCR, western blotting and immunohistochemistry confirmed repression of sGC, and myograph experiments disclosed curtailed relaxation in response to the sGC activator BAY 41‐2272. To decipher underlying mechanisms we analyzed abundance of transcription factor binding motifs in promoters of differentially expressed genes, and identified enrichment (P=0.01) of RBPJ sites. RBPJ (recombination signal binding protein for immunoglobulin kappa J region or CBF1) is a core component of the NOTCH signaling pathway, and we accordingly found that the NOTCH caoctivators FRYL (FRY like transcriptional coactivator) and MAML2 (mastermind like transcriptional coactivator 2) were reduced in hypertension. Gain and loss of function experiments in smooth muscle from mice and humans demonstrated that JAG/NOTCH signaling controls sGC expression together with the coactivators MAML2 and FRYL. We also found altered expression of sGC, correlating with differential expression of MAML2, in stroke prone and spontaneously hypertensive rats. Finally, using RNA‐Seq data from the human coronary artery, we found compelling correlations between JAG1, NOTCH3, MAML2 and FRYL and the sGC subunits GUCY1A3 and GUCY1B3. Taken together, these studies suggest that NOTCH signaling provides a constitutive drive on expression of the major nitric oxide receptor (GUCY1A3/GUCY1B3) in systemic arteries from mice and humans, and that this homeostatic control mechanism is disturbed in hypertension.Support or Funding InformationThis study was supported by The Swedish Research Council K2015‐65X‐22662‐01‐03, The Crafoord Foundation and SMARTER a Marie Curie Initial Training Network.
Glucocorticoid Sensitivity and Systolic Blood Pressure During Graded Submaximal Exercise
Authors: Del Corral Pedro , Mancol Faith Laureen V , DePasquale John , Haug Andrew , Teelucksingh Surujpal 
Published: November 2023

BackgroundThe exaggerated systolic blood pressure (SBP) response to exercise predicts future hypertension and coronary artery disease. Hypertension has been associated to an increase in glucocorticoid sensitivity. Little is known about the effects of glucocorticoid sensitivity on the exaggerated SBP response to submaximal exercise.PURPOSEThe aim of this study was to examine the relationship between glucocorticoid sensitivity and the systolic blood pressure response to graded submaximal exercise (GSE) on a cycle ergometer.METHODSTwenty two (19M, 3F) non‐hypertensive subjects (111.3/64.3 mmHg ± 1.9/1.4) underwent the dermal vasoconstrictor assay, using beclomethasone dipropionate, to determine glucocorticoid sensitivity, and subjects completed the GSE test with serial SBP measurements. Pearson's correlations were used to examine the relationship between glucocorticoid sensitivity and peak‐SBP. Subjects were dichotomized for glucocorticoid sensitivity, the upper and lower tertiles (11.4 ± 0.8 vs 3.2 ± 0.8, respectively; p<0.05) were compared for peak SBP during GSE and for rest to peak‐BP (Δ‐SBP).RESULTSThere was a moderate association between dermal glucocorticoid sensitivity and peak SBP (r = 0.550, p<0.05), and Δ‐SBP (r = 0.497, p<0.05). Subjects on the upper tertile for glucocorticoid sensitivity had significantly higher peak SBP (189.2 ± 5.6 mmHg vs 155.5 ± 5.2 mmHg, p<0.05) and Δ‐SBP (76.9 ± 5.9 mmHg vs 48.2 ± 5.0 mmHg, p<0.05), compared to subjects on the lower tertile.CONCLUSIONSThese findings suggest that individuals with a high glucocorticoid sensitivity, as suggested by the dermal vasoconstrictor assay SCORE, have a greater submaximal exercise peak SBP and Δ‐SBP, compared to those with a low glucocorticoid sensitivity.Support or Funding InformationBenedictine University Summer Research Program
Arterial smooth muscle cell PKD2 (TRPP1) channels control systemic blood pressure
Authors: Bulley Simon , Leo M. Dennis , Hasan Raquibul , Fernandez‐Pena Carlos , Evanson Kirk W. , Burris Sarah K. , Wang Qian , Kuruvilla Korah P. , Jaggar Jonathan H. 
Published: November 2023

Autosomal dominant polycystic kidney disease (ADPKD), an inherited condition that affects approximately 1 in 800 people, occurs due to mutations in either PKD1 or PKD2 proteins. Although ADPKD is characterized by the formation of kidney cysts, patients suffer from cardiovascular diseases, including hypertension, often with no alteration in renal function. PKD2 is a six transmembrane domain transient receptor potential (TRP) channel that is also termed TRPP1. Recent evidence suggests that PKD2 is expressed in arterial smooth muscle cells, but functional significance is poorly understood. Similarly unclear is the regulation of blood pressure by arterial smooth muscle cell TRP channels. Here, we generated a novel, conditional smooth muscle‐specific PKD2 knockout (PKD2sm−/−) mouse model to investigate the regulation of systemic artery contractility and blood pressure by PKD2. PKD2 channel expression was abolished in arterial smooth muscle cells of PKD2sm−/− mice, whereas PKD1, TRPC6, TRPM4, CaV1.2 or ANO1 proteins were similar to those in PKD2fl/fl controls. Telemetry demonstrated that systemic blood pressure was lower in PKD2sm−/− mice than in PKD2fl/fl controls. Experiments that measured cardiac function, plasma and urine electrolytes, plasma hormones and histological assessment of kidney structure identified no differences in PKD2sm−/− and PKD2fl/fl mice. Vasoconstriction stimulated by phenylephrine (PE), an α1‐adrenergic receptor agonist, and intravascular pressure were both attenuated in resistance‐size systemic arteries from PKD2sm−/− mice, when compared to PKD2fl/fl controls. PE‐induced non‐selective cation current (ICat) activation was smaller in systemic artery smooth muscle cells of PKD2sm−/− mice. Application of patch pressure activated single non‐selective cation channels in systemic artery smooth muscle cells of PKDfl/fl mice that were absent in cells of PKD2sm−/− mice. These data suggest that PE and intravascular pressure stimulate PKD2 channels in systemic artery smooth muscle cells, leading to vasoconstriction and an increase in blood pressure.Support or Funding InformationNIH/NHLBI grants to Jonathan H. Jaggar. American Heart Association grants to Simon Bulley and M. Dennis Leo.
The ankle‐brachial pressure index and it's correlation with oxidative stress in Acute Myocardial Infarction
Authors: Gulati Rajiv , Siddiqui Anwar Hasan , Parvez Anjum , Islam Najmul 
Published: November 2023

BackgroundIn recent years significant attention has been paid in identifying markers of increased cardiovascular risk, in particular the coronary artery disease. The ankle‐brachial pressure index (ABI), an easily accessible, inexpensive bedside test can be a significant tool to assess the vascular risk in symptomatic and asymptomatic cardiovascular patients. Oxidative stress and lipid peroxidation is thought to play a crucial role in the generation of atherosclerotic lesions of Acute Myocardial Infarction (AMI).ObjectiveTo determine the association between an abnormal ankle brachial index (ABI) and oxidative stress in coronary artery disease (CAD).MethodThe study population included 160 subjects divided in two groups, 90 patients with AMI and 70 age and sex matched healthy subjects as controls. Ankle Brachial Pressure Index (ABI) was measured in all the subjects along with their LDH level. Antioxidant status of the individuals was determined by measuring the serum levels of Glutathione Peroxidase (GPx) and Superoxide Dismutase (SOD). Estimation of Malondialdehyde (MDA), a marker of lipid peroxidation was used as a surrogate marker of free radical activity.ResultA significantly low ABI (<0.9) was observed among the AMI patients as compared to healthy controls. Moreover the ABI showed negative correlation with the level of LDH amd MDA in the AMI patient. GPx and SOD were positively correlated with ABI.ConclusionABI calculation would be able to identify more patients at high risk and as such it should be considered routine investigation for cardiovascular risk prediction.Support or Funding InformationTRAVEL GRANT AND REGISTRATION GRANT FINANCIAL ASSISTANCE REQUIRED TO TRAVEL TO CHICAGO.REQUEST TO ORGANIZERS TO PROVIDE ASSISTANCE.
The Role of PPAR‐g in Shp1‐Mediated Regulation of Glucose Homeostasis in the Liver
Authors: Gomez Lilian , Lavallée‐Bourget Marie‐Hélène , Forest Marie‐Pier , Schwab Michael , Bellmann Kerstin , Sola‐Penna Mauro , Deshaies Yves , Marette André 
Published: November 2023

The protein‐tyrosine phosphatase Shp1 plays a central role in high‐fat diet (HFD)‐induced insulin resistance. This enzyme, which negatively regulates insulin action on glucose homeostasis, is upregulated in metabolic tissues, such as liver, muscle and adipose tissue, of mice submitted to HFD. Hepatocyte‐specific Shp1 knockout mice (Ptpn6H‐KO) submitted to HFD develop hepatic steatosis but show less hepatic insulin resistance. These effects might be due to the observed attenuation of HFD‐induced inflammation and liver damage. Moreover, while Ptpn6H‐KO mice present a significant increase in PPARg expression, overexpression of Shp1 reduces the activity of this nuclear receptor. The aim of the present study is to evaluate the role of PPARg on the amelioration of liver inflammation in HFD‐fed Ptpn6H‐KO mice. For this, male Ptpn6H‐KO mice were kept on standard diet (SD) or HFD for 18 weeks. During the last 4 weeks the animals were treated with a very low dose of rosiglitazone, a known PPARg agonist. Rosiglitazone‐treated Ptpn6H‐KO mice showed an improvement in glucose tolerance without a significant change in insulinemia during oral glucose tolerance test. Insulin‐induced Akt phosphorylation, was increased by rosiglitazone in the Ptpn6H‐KO mice, which may partially explain the amelioration in glucose tolerance. Despite the fact that rosiglitazone increased hepatic steatosis in Ptpn6H‐KO mice, the drug also augmented the levels of the anti‐inflammatory cytokine, IL‐10. However, rosiglitazone did not improve the pattern of pro‐inflammatory cytokines in the liver. Altogether, our data support that Shp1 effects on glucose homeostasis involve the activation of PPARg, but the complete role of these players on liver inflammation has yet to be elucidated.Support or Funding InformationCanadian Institutes of Health Research and CNPq