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52. Endothelial deficiency of insulin-like growth factor-1 receptor reduces endothelial barrier function and promotes atherosclerosis in Apoe-deficient mice

Author

Higashi, Yusuke, primary, Sukhanov, Sergiy, additional, Shai, Shaw-Yung, additional, Danchuk, Svitlana, additional, Snarski, Patricia, additional, Li, Zhaohui, additional, Hou, Xuwei, additional, Hamblin, Milton H., additional, Woods, T. Cooper, additional, Wang, Meifang, additional, Wang, Derek, additional, Yu, Hong, additional, Korthuis, Ronald J., additional, Yoshida, Tadashi, additional, and Delafontaine, Patrice, additional

Published
2020
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71. Angiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscle

Author

Silva, Kleiton Augusto Santos, primary, Ghiarone, Thaysa, additional, Schreiber, Kathy, additional, Grant, DeAna, additional, White, Tommi, additional, Frisard, Madlyn I., additional, Sukhanov, Sergiy, additional, Chandrasekar, Bysani, additional, Delafontaine, Patrice, additional, and Yoshida, Tadashi, additional

Published
2019
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73. RECK suppresses interleukin‐17/TRAF3IP2‐mediated MMP‐13 activation and human aortic smooth muscle cell migration and proliferation

Author

Mummidi, Srinivas, primary, Das, Nitin A, additional, Carpenter, Andrea J, additional, Yoshida, Tadashi, additional, Mostany, Ricardo, additional, Izadpanah, Reza, additional, Higashi, Yusuke, additional, Sukhanov, Sergiy, additional, Delafontaine, Patrice, additional, Siebenlist, Ulrich, additional, Randy, Scott Rector, additional, and Bysani, Chandrasekar, additional

Published
2019
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77. Endothelial deficiency of insulin-like growth factor-1 receptor reduces endothelial barrier function and promotes atherosclerosis in Apoe-deficient mice.

Author

Yusuke Higashi, Sukhanov, Sergiy, Shaw-Yung Shai, Danchuk, Svitlana, Snarski, Patricia, Zhaohui Li, Xuwei Hou, Hamblin, Milton H., Woods, T. Cooper, Meifang Wang, Derek Wang, Hong Yu, Korthuis, Ronald J., Tadashi Yoshida, and Delafontaine, Patrice

Subjects
ADHERENS junctions, CELL junctions, ATHEROSCLEROSIS, APOLIPOPROTEIN E, HIGH-fat diet, CADHERINS
Abstract

First published August 14, 2020; doi:10.1152/ajpheart.00064.2020.--Insulin-like growth factor-1 (IGF-1) decreases atherosclerosis in apolipoprotein E (Apoe)-deficient mice when administered systemically. However, mechanisms for its atheroprotective effect are not fully understood. We generated endothelium-specific IGF-1 receptor (IGF1R)-deficient mice on an Apoe-deficient background to assess effects of IGF-1 on the endothelium in the context of hyperlipidemia-induced atherosclerosis. Endothelial deficiency of IGF1R promoted atherosclerotic burden, when animals were fed on a high-fat diet for 12 wk or normal chow for 12 mo. Under the normal chow feeding condition, the vascular relaxation response to acetylcholine was increased in the endothelial IGF1R-deficient aorta; however, feeding of a high-fat diet substantially attenuated the relaxation response, and there was no difference between endothelial IGF1R-deficient and control mice. The endothelium and its intercellular junctions provide a barrier function to the vasculature. In human aortic endothelial cells, IGF-1 upregulated occludin, claudin 5, VE-cadherin, JAM-A, and CD31 expression levels, and vice versa, specific IGF1R inhibitor, picropodophyllin, an IGF1R-neutralizing antibody (IR3), or siRNA to IGF1R abolished the IGF-1 effects on junction and adherens proteins, suggesting that IGF-1 promoted endothelial barrier function. Moreover, endothelial transwell permeability assays indicated that inhibition of IGF-1 signaling elevated solute permeability through the monolayer of human aortic endothelial cells. In summary, endothelial IGF1R deficiency increases atherosclerosis, and IGF-1 positively regulates tight junction protein and adherens junction protein levels and endothelial barrier function. Our findings suggest that the elevation of the endothelial junction protein level is, at least in part, the mechanism for antiatherogenic effects of IGF-1. [ABSTRACT FROM AUTHOR]

Published
2020
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78. Association of QT-Prolonging Medication Use in CKD with Electrocardiographic Manifestations

Author

Snitker, Soren, Doerfler, Rebecca M., Soliman, Elsayed Z., Deo, Rajat, St. Peter, Wendy L., Kramlik, Susan, Fischer, Michael J., Navaneethan, Sankar, Delafontaine, Patrice, Jaar, Bernard G., Ojo, Akinlolu, Makos, Gail K., Slaven, Anne, Weir, Matthew R., Zhan, Min, and Fink, Jeffrey C.

Subjects
Male, Epidemiology, 030232 urology & nephrology, Amiodarone, 030204 cardiovascular system & hematology, Citalopram, Critical Care and Intensive Care Medicine, QT interval, Diabetes Complications, 03 medical and health sciences, chemistry.chemical_compound, Electrocardiography, 0302 clinical medicine, Furosemide, Heart Rate, Metolazone, Fluoxetine, Heart rate, medicine, Humans, Renal Insufficiency, Chronic, Diuretics, Aged, Transplantation, medicine.diagnostic_test, business.industry, Venlafaxine Hydrochloride, Heart, Proton Pump Inhibitors, Original Articles, Middle Aged, chemistry, Nephrology, Anesthesia, Hydroxyzine, Spironolactone, Histamine H1 Antagonists, Antidepressive Agents, Second-Generation, Female, Electrical conduction system of the heart, business, Anti-Arrhythmia Agents, medicine.drug
Abstract

Background and objectives Several drugs used in CKD can prolong electrocardiographic conduction. We examined the use of electrocardiogram QT-prolonging medications in predialysis CKD and their association with QT duration. Design, setting, participants, & measurements In total, 3252 Chronic Renal Insufficiency Cohort participants with at least one study electrocardiogram between 2003 and 2011 were included. QT-prolonging medications used in 100 or more visits (n=16,451 visits) along with diuretics and proton pump inhibitors, given their potential for electrolyte disturbances, were examined for QT interval prolongation. Results Mean QT interval corrected for heart rate was at 414±21 (±SD) milliseconds and prolonged (≥450 milliseconds) in 4.6% of electrocardiograms. QT interval corrected for heart rate was inversely related to serum potassium and calcium. Medications classified as QT prolonging were taken at 76% of visits, with two or more of these taken at 33% of visits. Of 30 medications examined, eight were associated with statistically significant QT interval corrected for heart rate prolongation after adjustment for comorbidities, potassium, and calcium, including amiodarone (+10±2 milliseconds), metolazone (+7±2 milliseconds), fluoxetine (+4±1 milliseconds), citalopram (+4±1 milliseconds), hydroxyzine (+4±1 milliseconds), escitalopram (+3±2 milliseconds), venlafaxine (+3±1 milliseconds), and furosemide (+3±0 milliseconds). Potassium-depleting diuretics were associated with minimal decrements in potassium (between 0.1 and 0.3 mEq/L) and smaller changes in calcium. Diuretics associated with a change in QT interval corrected for heart rate before adjustment for potassium and calcium were metolazone (+8±3 milliseconds), furosemide (+4±1 milliseconds), and spironolactone (−3±3 milliseconds). Most of the QT prolongation associated with metolazone and furosemide, but not spironolactone, remained after adjustment for potassium and calcium. Proton pump inhibitors were not associated with QT prolongation. Conclusions Use of medications associated with QT prolongation is common in CKD; the safety implications of these findings should be considered in these high-risk patients. Podcast This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_09_CJASNPodcast_17_09_b.mp3

Published
2017

79. Drug-eluting stents versus bare-metal stents in saphenous vein grafts: a double-blind, randomised trial

Author

Brilakis, Emmanouil S, primary, Edson, Robert, additional, Bhatt, Deepak L, additional, Goldman, Steven, additional, Holmes, David R, additional, Rao, Sunil V, additional, Shunk, Kendrick, additional, Rangan, Bavana V, additional, Mavromatis, Kreton, additional, Ramanathan, Kodangudi, additional, Bavry, Anthony A, additional, Garcia, Santiago, additional, Latif, Faisal, additional, Armstrong, Ehrin, additional, Jneid, Hani, additional, Conner, Todd A, additional, Wagner, Todd, additional, Karacsonyi, Judit, additional, Uyeda, Lauren, additional, Ventura, Beverly, additional, Alsleben, Aaron, additional, Lu, Ying, additional, Shih, Mei-Chiung, additional, Banerjee, Subhash, additional, Ahmed, Bina, additional, Ratliff, D Michelle, additional, Ricciardi, Mark, additional, Sheldon, Mark, additional, Icenogle, Milton, additional, Snider, Richard, additional, Ardati, Amer, additional, Nallamothu, Brahmajee, additional, Duvernoy, Claire, additional, Menees, Daniel S, additional, Gurm, Hitinder, additional, Thomas, Michael P, additional, Grossman, Paul, additional, Owen, Kristine, additional, Topaz, On, additional, Kumar, Gautam, additional, Block, Peter, additional, Zidar, David A, additional, Bezerra, Hiram, additional, Goldberg, Jonathan, additional, Ortiz, Jose, additional, Jozic, Joseph, additional, Osman, Mohammed, additional, Rosenthal, Noah, additional, Parikh, Sahil A, additional, Lassar, Tom A, additional, Chan, Albert, additional, Kumar, Arun, additional, Aggarwal, Kul, additional, Cyrus, Tillmann, additional, Brilakis, Emmanouil S, additional, Grodin, Jerrold, additional, Hattler, Brack, additional, Casserly, Ivan, additional, Messenger, John, additional, Kim, Michael, additional, Rogers, R Kevin, additional, Waldo, Stephen, additional, Tsai, Thomas, additional, Morris, Kenneth, additional, Krucoff, Mitchell, additional, Rao, Sunil, additional, Povsic, Thomas J, additional, Jones, William S, additional, Bavry, Anthony, additional, Choi, Calvin, additional, Park, Ki, additional, Liu, MD, Jayson, additional, Kar, Biswajit, additional, Paniagua, David, additional, Breall, Jeffrey, additional, Bolad, Islam, additional, Mukerji, Rita, additional, Subbarao, Roopa, additional, Abdel-Latif, Ahmed, additional, Booth, David C, additional, Ziada, Khaled M, additional, Rajan, Lawrence, additional, Hakeem, Abdul, additional, Uretsky, Barry F, additional, Agrawal, Mayank, additional, Sachdeva, Rajesh, additional, Ahmed, Zubair, additional, McGee, Jesse, additional, Shah, Rahman, additional, Sharma, Alok, additional, McFalls, Edward, additional, Siddiqui, Rizwan, additional, Adabag, Selcuk, additional, Bertog, Stefan, additional, Irimpen, Anand, additional, Baldwin, Drew, additional, Abi Rafeh, Nidal, additional, Mogabgab, Owen, additional, Delafontaine, Patrice, additional, Lorin, Jeffrey, additional, Sedlis, Steven, additional, Schechter, Eliot, additional, Abu-Fadel, Mazen, additional, Rousan, Talla, additional, Thadani, Udho, additional, Malik, Fady, additional, Zimmet, Jeffrey, additional, Chou, Tony, additional, Beatty, Alexis, additional, Lehmann, Kenneth, additional, Stadius, Michael, additional, Klein, Andrew, additional, Rowe, Caroline, additional, Taniuchi, Megumi, additional, Klein, Andrew J, additional, Forsberg, Michael, additional, Kapoor, Divya, additional, Juneman, Elizabeth, additional, Truong, Huu Tam, additional, Lotun, Kapildeo, additional, Tsuda, Ryan, additional, Thai, Sergio, additional, Thai, Hoang, additional, Lu, David, additional, Papademetriou, Vasilios, additional, Faxon, David, additional, Croce, Kevin, additional, Elmariah, Sammy, additional, and Kinlay, Scott, additional

Published
2018
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83. Effect of uniaxial, cyclic stretch on the morphology of monocytes/macrophages in culture

Author

Matsumoto, Takeo, Delafontaine, Patrice, Schnetzer, Karen J., Tong, Betty C., and Nerem, Robert M.

Subjects
Monocytes -- Research, Macrophages -- Research, Engineering and manufacturing industries, Science and technology
Abstract

The effects of cyclic stretch on the morphology of monocytes/macrophages recruited into the sub-endothelial region, are studied. The monocyte-like cell line (U937, ATCC) and the rat peritoneal macrophage (RPM) were the two different cell types utilized. Findings show that U937 cells are more sensitive to the cyclic stretch that RPMs. However, the total percentage of highly differentiated cells was not affected by the cyclic stretch.

Published
1996

84. The Nox1/4 dual inhibitor GKT137831 or Nox4 knockdown inhibits Angiotensin-II-induced adult mouse cardiac fibroblast proliferation and migration. AT1 physically associates with Nox4

Author

Somanna, Naveen K., Valente, Anthony J., Krenz, Maike, Fay, William P., Delafontaine, Patrice, and Chandrasekar, Bysani

Subjects
Male, Aging, Pyridines, Pyridones, Article, Receptor, Angiotensin, Type 1, Cell Movement, Animals, Humans, Pyrazolones, Cell Proliferation, urogenital system, Angiotensin II, Myocardium, Interleukin-18, NF-kappa B, NADPH Oxidases, Fibroblasts, Enzyme Activation, Mice, Inbred C57BL, Transcription Factor AP-1, Oxidative Stress, Matrix Metalloproteinase 9, NADPH Oxidase 4, Gene Knockdown Techniques, cardiovascular system, Pyrazoles, Reactive Oxygen Species, Protein Binding
Abstract

Both oxidative stress and inflammation contribute to chronic hypertension-induced myocardial fibrosis and adverse cardiac remodeling. Here we investigated whether angiotensin (Ang)-II-induced fibroblast proliferation and migration are NADPH oxidase (Nox) 4/ROS and IL-18 dependent. Our results show that the potent induction of mouse cardiac fibroblast (CF) proliferation and migration by Ang-II is markedly attenuated by Nox4 knockdown and the Nox inhibitor DPI. Further, Nox4 knockdown and DPI pre-treatment attenuated Ang-II-induced IL-18, IL-18Rα and collagen expression, and MMP9 and LOX activation. While neutralization of IL-18 blunted Ang-II-induced CF proliferation and migration, knockdown of MMP9 attenuated CF migration. The antioxidant NAC and the cell-permeable SOD mimetics Tempol, MnTBAP, and MnTMPyP attenuated oxidative stress and inhibited CF proliferation and migration. The Nox1/Nox4 dual inhibitor GKT137831 also blunted Ang-II-induced H2 O2 production and CF proliferation and migration. Further, AT1 bound Nox4, and Ang-II enhanced their physical association. Notably, GKT137831 attenuated the AT1/Nox4 interaction. These results indicate that Ang-II induces CF proliferation and migration in part via Nox4/ROS-dependent IL-18 induction and MMP9 activation, and may involve AT1/Nox4 physical association. Thus, either (i) neutralizing IL-18, (ii) blocking AT1/Nox4 interaction or (iii) use of the Nox1/Nox4 inhibitor GKT137831 may have therapeutic potential in chronic hypertension-induced adverse cardiac remodeling.

Published
2015

87. Abstract 13854: Micro-RNA Regulation of Collagen Production by Vascular Smooth Muscle Cells Mediated by La Ribonucleoprotein Domain Family Member 6: Potential Mechanisms Underlying Stable Phenotype of Atherosclerotic Plaque by Insulin-like Growth Factor 1

Author

Higashi, Yusuke, primary, Danchuk, Svitlana, additional, Sukhanov, Sergiy, additional, Blackstock, Christopher, additional, Li, Zhaohui, additional, Snarski, Patricia, additional, and Delafontaine, Patrice, additional

Published
2016
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88. Kansas City Cardiomyopathy Questionnaire Score Is Associated With Incident Heart Failure Hospitalization in Patients With Chronic Kidney Disease Without Previously Diagnosed Heart Failure: Chronic Renal Insufficiency Cohort Study

Author

Mishra, Rakesh K, Yang, Wei, Roy, Jason, Anderson, Amanda H, Bansal, Nisha, Chen, Jing, DeFilippi, Christopher, Delafontaine, Patrice, Feldman, Harold I, Kallem, Radhakrishna, Kusek, John W, Lora, Claudia M, Rosas, Sylvia E, Go, Alan S, Shlipak, Michael G, and CRIC Study Investigators

Subjects
Adult, Male, Time Factors, Kidney Disease, Left, Medical Physiology, Renal and urogenital, heart failure, Cardiorespiratory Medicine and Haematology, Cardiovascular, Risk Assessment, renal insufficiency, Young Adult, Natriuretic Peptide, Clinical Research, Risk Factors, Surveys and Questionnaires, Ventricular Dysfunction, Odds Ratio, Humans, Ventricular Function, 2.1 Biological and endogenous factors, Prospective Studies, Chronic, Aetiology, Proportional Hazards Models, Aged, Chi-Square Distribution, Incidence, Brain, Hypertrophy, Middle Aged, Myocardial Contraction, Peptide Fragments, United States, Left Ventricular, Hospitalization, Logistic Models, Heart Disease, Cardiovascular System & Hematology, CRIC Study Investigators, Multivariate Analysis, Disease Progression, Female, Biochemistry and Cell Biology, Cardiomyopathies, Biomarkers
Abstract

BackgroundChronic kidney disease is a risk factor for heart failure (HF). Patients with chronic kidney disease without diagnosed HF have an increased burden of symptoms characteristic of HF. It is not known whether these symptoms are associated with occurrence of new onset HF.Methods and resultsWe studied the association of a modified Kansas City Cardiomyopathy Questionnaire with newly identified cases of hospitalized HF among 3093 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study who did not report HF at baseline. The annually updated Kansas City Cardiomyopathy Questionnaire score was categorized into quartiles (Q1-4) with the lower scores representing the worse symptoms. Multivariable-adjusted repeated measure logistic regression models were adjusted for demographic characteristics, clinical risk factors for HF, N-terminal probrain natriuretic peptide level and left ventricular hypertrophy, left ventricular systolic and diastolic dysfunction. Over a mean (±SD) follow-up period of 4.3±1.6 years, there were 211 new cases of HF hospitalizations. The risk of HF hospitalization increased with increasing symptom quartiles; 2.62, 1.85, 1.14, and 0.74 events per 100 person-years, respectively. The median number of annual Kansas City Cardiomyopathy Questionnaire assessments per participant was 5 (interquartile range, 3-6). The annually updated Kansas City Cardiomyopathy Questionnaire score was independently associated with higher risk of incident HF hospitalization in multivariable-adjusted models (odds ratio, 3.30 [1.66-6.52]; P=0.001 for Q1 compared with Q4).ConclusionsSymptoms characteristic of HF are common in patients with chronic kidney disease and are associated with higher short-term risk for new hospitalization for HF, independent of level of kidney function, and other known HF risk factors.

Published
2015

89. Angiotensin II suppresses autophagy and disrupts ultrastructural morphology and function of mitochondria in mouse skeletal muscle.

Author

Santos Silva, Kleiton Augusto, Ghiarone, Thaysa, Schreiber, Kathy, Grant, De Ana, White, Tommi, Frisard, Madlyn I., Sukhanov, Sergiy, Chandrasekar, Bysani, Delafontaine, Patrice, and Tadashi Yoshida

Subjects
ANGIOTENSIN II, SKELETAL muscle, CHRONIC wasting disease, AUTOPHAGY, MORPHOLOGY, MICROTUBULE-associated proteins
Abstract

Angiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5'-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels. [ABSTRACT FROM AUTHOR]

Published
2019
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92. Insulin-Like Growth Factor-1 Receptor Deficiency in Macrophages Accelerates Atherosclerosis and Induces an Unstable Plaque Phenotype in Apolipoprotein E–Deficient Mice

Author

Higashi, Yusuke, primary, Sukhanov, Sergiy, additional, Shai, Shaw-Yung, additional, Danchuk, Svitlana, additional, Tang, Richard, additional, Snarski, Patricia, additional, Li, Zhaohui, additional, Lobelle-Rich, Patricia, additional, Wang, Meifang, additional, Wang, Derek, additional, Yu, Hong, additional, Korthuis, Ronald, additional, and Delafontaine, Patrice, additional

Published
2016
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95. Abstract 17298: Association of Left Atrial Size and Incident Heart Failure and All-cause Death: The Chronic Renal Insufficiency Cohort (CRIC) Study

Author

Zamani, Payman, primary, Hsu, Jesse Y, additional, Keane, Martin G, additional, Bansal, Nisha, additional, Delafontaine, Patrice, additional, Go, Alan S, additional, He, Jiang, additional, Kawut, Steven M, additional, Ky, Bonnie, additional, Lora, Claudia M, additional, Seliger, Stephen L, additional, Sharif, Tariq, additional, Shlipak, Michael, additional, Tao, Kelvin, additional, Townsend, Raymond R, additional, Feldman, Harold I, additional, and Deo, Rajat, additional

Published
2015
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98. Rapid estrogen receptor-α signaling mediated by ERK activation regulates vascular tone in male and ovary-intact female mice.

Author

Seong Chul Kim, Boese, Austin C., Moore, Matthew H., Cleland, Rea M., Lin Chang, Delafontaine, Patrice, Ke-Jie Yin, Jean-Pyo Lee, and Hamblin, Milton H.

Subjects
VASCULAR diseases, ESTROGEN receptors, CELLULAR signal transduction
Abstract

Estrogen has been shown to affect vascular reactivity. Here, we assessed the estrogen receptor-α (ERα) dependency of estrogenic effects on vasorelaxation via a rapid nongenomic pathway in both male and ovary-intact female mice. We compared the effect of a primary estrogen, 17β-estradiol (E2) or 4,4',4''-(4-propyl-[1H]pyrazole-1,3,5-triyl)tris-phenol (PPT; selective ERα agonist). We found that E2 and PPT induced greater aortic relaxation in female mice than in male mice, indicating ERα mediation, which was further validated by using ERα antagonism. Treatment with 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy) phenol]-1H-pyrazole dihydrochloride (MPP dihydrochloride; ERα antagonist) attenuated PPT-mediated vessel relaxation in both sexes. ERα-mediated vessel relaxation was further validated by the absence of significant PPT-mediated relaxation in aortas isolated from ERα knockout mice. Treatment with a specific ERK inhibitor, PD- 98059, reduced E2-induced vessel relaxation in both sexes but to a lesser extent in female mice. Furthermore, PD-98059 prevented PPTinduced vessel relaxation in both sexes. Both E2 and PPT treatment activated ERK as early as 5-10 min, which was attenuated by PD-98059 in aortic tissue, cultured primary vascular smooth muscle cells (VSMCs), and endothelial cells (ECs). Aortic rings denuded of endothelium showed no differences in vessel relaxation after E2 or PPT treatment, implicating a role of ECs in the observed sex differences. Here, our results are unique to show estrogen-stimulated rapid ERα signaling mediated by ERK activation in aortic tissue, as well as VSMCs and ECs in vitro, in regulating vascular function by using side-by-side comparisons in male and ovary-intact female mice in response to E2 or PPT. [ABSTRACT FROM AUTHOR]

Published
2018
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