Featured Publications
Prior Exposure to Experimental Preeclampsia Increases Atherosclerotic Plaque Inflammation in Atherogenic Mice—Brief Report
Biwer L, Man J, Camarda N, Carvajal B, Karumanchi S, Jaffe I. Prior Exposure to Experimental Preeclampsia Increases Atherosclerotic Plaque Inflammation in Atherogenic Mice—Brief Report. Arteriosclerosis Thrombosis And Vascular Biology 2024, 44: 946-953. PMID: 38450510, PMCID: PMC10978246, DOI: 10.1161/atvbaha.123.320474.Peer-Reviewed Original ResearchConceptsAtherosclerotic plaque inflammationLDLr-KO micePlaque inflammationAortic root plaque sizeEvidence of premature atherosclerosisFlow cytometryRisk factorsHistory of preeclampsiaIncreased risk of myocardial infarctionPreexisting risk factorsRisk of myocardial infarctionFed high-fat dietExpression of IGFBP6Mouse atherosclerosis modelHigh-density lipoproteinAortic cytokinesNecrotic core areaPreeclampsia exposureSerum sFlt1Normotensive pregnanciesHigh-fat dietPreeclampsia pregnanciesCD3+T cellsHigh-fat feedingLow-density lipoproteinSmooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia
Biwer L, Lu Q, Ibarrola J, Stepanian A, Man J, Carvajal B, Camarda N, Zsengeller Z, Skurnik G, Seely E, Karumanchi S, Jaffe I. Smooth Muscle Mineralocorticoid Receptor Promotes Hypertension After Preeclampsia. Circulation Research 2023, 132: 674-689. PMID: 36815487, PMCID: PMC10119809, DOI: 10.1161/circresaha.122.321228.Peer-Reviewed Original ResearchConceptsBlood pressureSMC-MRHypertensive stimuliBP responseSmooth Muscle Cell Mineralocorticoid ReceptorsAngII type 1 receptorType 1 receptor expressionMR transcriptional activityIncreased cardiovascular riskElevated blood pressureEnd-organ damageHigh salt intakeHigh blood pressureRisk of hypertensionType 1 receptorSoluble VEGF receptorAngII infusionPrior preeclampsiaMR antagonismCardiovascular riskNormotensive pregnanciesSalt dietAortic stiffnessSalt intakeOrgan damageMineralocorticoid and Estrogen Receptors in Endothelial Cells Coordinately Regulate Microvascular Function in Obese Female Mice
Biwer L, Carvajal B, Lu Q, Man J, Jaffe I. Mineralocorticoid and Estrogen Receptors in Endothelial Cells Coordinately Regulate Microvascular Function in Obese Female Mice. Hypertension 2021, 77: 2117-2126. PMID: 33934622, PMCID: PMC8119365, DOI: 10.1161/hypertensionaha.120.16911.Peer-Reviewed Original ResearchEndothelial calreticulin deletion impairs endothelial function in aged mice
Biwer L, Askew-Page H, Hong K, Milstein J, Johnstone S, Macal E, Good M, Bagher P, Sonkusare S, Isakson B. Endothelial calreticulin deletion impairs endothelial function in aged mice. AJP Heart And Circulatory Physiology 2020, 318: h1041-h1048. PMID: 32196361, PMCID: PMC7346539, DOI: 10.1152/ajpheart.00586.2019.Peer-Reviewed Original ResearchConceptsVascular functionTauroursodeoxycholic acidMesenteric arteryAged miceCalcium signalsImpaired endothelial-dependent vasodilationThird-order mesenteric arteriesEndothelial cellsEndothelial-dependent vasodilationIncubation of arteriesImpairs endothelial functionSmall resistance arteriesMultifunctional calcium binding proteinER stress inhibitor tauroursodeoxycholic acidWk of ageEndoplasmic reticulum stressPE constrictionEndothelial functionVasodilatory functionResistance arteriesCalcium binding proteinAgonist carbacholClinical trialsMuscarinic stimulationVasodilationLoss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction
Krüger N, Biwer L, Good M, Ruddiman C, Wolpe A, DeLalio L, Murphy S, Macal E, Ragolia L, Serbulea V, Best A, Leitinger N, Harris T, Sonkusare S, Gödecke A, Isakson B. Loss of Endothelial FTO Antagonizes Obesity-Induced Metabolic and Vascular Dysfunction. Circulation Research 2019, 126: 232-242. PMID: 31801409, PMCID: PMC7007767, DOI: 10.1161/circresaha.119.315531.Peer-Reviewed Original ResearchConceptsMyogenic toneProstaglandin DResistance arteriesDeficient miceHigh-fat diet-induced glucose intoleranceDiet-induced glucose intoleranceObesity-induced hypertensionImpact of obesityPrevalence of obesityNew treatment optionsDevelopment of obesityHigh-fat dietRegulation of obesityDifferent cell typesCell typesGlucose intoleranceVascular alterationsVascular changesVascular dysfunctionControl miceInsulin resistanceTreatment optionsCardiovascular diseaseObesityArteryNon–Endoplasmic Reticulum–Based Calr (Calreticulin) Can Coordinate Heterocellular Calcium Signaling and Vascular Function
Biwer L, Good M, Hong K, Patel R, Agrawal N, Looft-Wilson R, Sonkusare S, Isakson B. Non–Endoplasmic Reticulum–Based Calr (Calreticulin) Can Coordinate Heterocellular Calcium Signaling and Vascular Function. Arteriosclerosis Thrombosis And Vascular Biology 2017, 38: 120-130. PMID: 29122814, PMCID: PMC5746467, DOI: 10.1161/atvbaha.117.309886.Peer-Reviewed Original ResearchConceptsThird-order mesenteric arteriesBlood pressureMesenteric arteryVascular functionCalcium signalingIEL holesApplication of CChMyoendothelial junctionsCalcium eventsER calciumSmooth muscle cellsInternal elastic laminaVascular reactivityResistance arteriesSmall arteriesSame arteryKnockout miceArteryΔ miceElastic laminaMuscle cellsEndoplasmic reticulum calciumMiceCALRCalcium signals
2022
Smooth muscle cell FTO regulates contractile function
Luse M, Krüger N, Good M, Biwer L, Serbulea V, Salamon A, Deaton R, Leitinger N, Gödecke A, Isakson B. Smooth muscle cell FTO regulates contractile function. AJP Heart And Circulatory Physiology 2022, 323: h1212-h1220. PMID: 36306211, PMCID: PMC9678421, DOI: 10.1152/ajpheart.00427.2022.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsThird-order mesenteric arteriesMuscle cellsObesity genesSmooth muscle contractilityRates of obesityHuman coronary arteriesCardiac myocyte contractilityPlasma reninBlood pressureMesenteric arteryMyogenic toneCoronary arteryFat massContractile functionMyocyte contractilityMuscle contractilityHeart rateSerum response factorMuscle depolarizationMouse body massContractilitySignificant decreaseCell deletionMice
2021
A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability
Maier-Begandt D, Comstra H, Molina S, Krüger N, Ruddiman C, Chen Y, Chen X, Biwer L, Johnstone S, Lohman A, Good M, DeLalio L, Hong K, Bacon H, Yan Z, Sonkusare S, Koval M, Isakson B. A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability. Science Signaling 2021, 14 PMID: 33653920, PMCID: PMC8011850, DOI: 10.1126/scisignal.aba2940.Peer-Reviewed Original ResearchConceptsRNA expression profilingHydrolysis of ATPPannexin-1 channelsExpression profilingArterial endothelial cellsEndothelial cellsArterial endotheliumVenous endothelial cellsBarrier functionProtein analysisLung vascular permeabilityPannexin-1Claudin compositionBarrier function impairmentProinflammatory cytokine TNFαEndothelial cell barrierTargetable pathwaysMurine veinCecal ligationCell barrierFunction impairmentInflammatory insultLife spanDeficient miceVascular leakMineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload–Induced Heart Failure
Kim S, Biwer L, Moss M, Man J, Aronovitz M, Martin G, Carrillo-Salinas F, Salvador A, Alcaide P, Jaffe I. Mineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload–Induced Heart Failure. Circulation Heart Failure 2021, 14: e007279. PMID: 33517669, PMCID: PMC7887087, DOI: 10.1161/circheartfailure.120.007279.Peer-Reviewed Original ResearchConceptsSmooth muscle cellsMR-intact littermatesAdverse cardiac remodelingMineralocorticoid receptorCardiac remodelingSMC-MRAortic constrictionPressure Overload-Induced Heart FailureInhibition of MRRole of MRPressure overload-induced hypertrophyCardiac blood supplyHeart failure hospitalizationCardiac capillary densityCoronary flow reserveTransverse aortic constrictionIntracardiac pressure measurementsOverload-induced hypertrophyFibrotic gene expressionFetal gene expressionFailure hospitalizationExercise capacityExercise testingEjection fractionHeart failure
2019
Gradual hypertension induction in middle‐aged Cyp1a1‐Ren2 transgenic rats produces significant impairments in spatial learning
Willeman M, Chawla M, Zempare M, Biwer L, Hoang L, Uprety A, Fitzhugh M, De Both M, Coleman P, Trouard T, Alexander G, Mitchell K, Barnes C, Hale T, Huentelman M. Gradual hypertension induction in middle‐aged Cyp1a1‐Ren2 transgenic rats produces significant impairments in spatial learning. Physiological Reports 2019, 7: e14010. PMID: 30916484, PMCID: PMC6436186, DOI: 10.14814/phy2.14010.Peer-Reviewed Original ResearchConceptsTransgenic ratsBlood pressureCyp1a1-Ren2 transgenic ratsRenin-dependent hypertensionImpact of hypertensionInduction of hypertensionSystolic blood pressureTransgenic rat modelMajor health concernAge of onsetRenal hypertrophyPrevalence increasesHypertension inductionRat modelHypertensionNeurological healthCollagen depositionLeft ventricleSensory functionBrain regionsCardiovascular systemSignificant impairmentRate of inductionMorris swim taskRats
2018
Vascular Mineralocorticoid Receptor: Evolutionary Mediator of Wound Healing Turned Harmful by Our Modern Lifestyle
Biwer L, Wallingford M, Jaffe I. Vascular Mineralocorticoid Receptor: Evolutionary Mediator of Wound Healing Turned Harmful by Our Modern Lifestyle. American Journal Of Hypertension 2018, 32: 123-134. PMID: 30380007, PMCID: PMC6331708, DOI: 10.1093/ajh/hpy158.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCardiovascular DiseasesDiet, High-FatEndothelial CellsEndothelium, VascularEvolution, MolecularHemodynamicsHumansLife StyleMuscle, Smooth, VascularMyocytes, Smooth MuscleReceptors, MineralocorticoidRisk FactorsSedentary BehaviorSignal TransductionSodium, DietaryVascular RemodelingWound HealingConceptsVascular mineralocorticoid receptorMineralocorticoid receptorActivation of MRDiffuse vascular damageMechanical vascular injuryHigh sodium dietBlood pressure maintenanceVascular tone regulationSmooth muscle cellsSodium dietBlood pressureMR activationVascular damagePhysical inactivityVascular injuryAdvanced ageTone regulationCardiovascular diseaseVascular remodelingSurvival advantageElectrolyte homeostasisVascular wallMuscle cellsModern lifestyleMR functionEndothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractility
Lechauve C, Butcher J, Freiwan A, Biwer L, Keith J, Good M, Ackerman H, Tillman H, Kiger L, Isakson B, Weiss M. Endothelial cell α-globin and its molecular chaperone α-hemoglobin–stabilizing protein regulate arteriolar contractility. Journal Of Clinical Investigation 2018, 128: 5073-5082. PMID: 30295646, PMCID: PMC6205378, DOI: 10.1172/jci99933.Peer-Reviewed Original Research
2016
Endoplasmic reticulum‐mediated signalling in cellular microdomains
Biwer L, Isakson B. Endoplasmic reticulum‐mediated signalling in cellular microdomains. Acta Physiologica 2016, 219: 162-175. PMID: 26973141, PMCID: PMC5018912, DOI: 10.1111/apha.12675.Peer-Reviewed Original ResearchConceptsEndoplasmic reticulumER-mitochondria junctionsImportant cellular organellesSpecific membrane proteinsSynthesis of proteinsLocalized proteinsER membraneCellular physiologyLipid signalingCellular signalingER architectureMembrane proteinsPhospholipid synthasesCellular stressCellular organellesCellular microdomainsOrganism homeostasisCytoplasmic networkSignalingPhospholipid transferIon channelsLipid synthesisTransfer proteinProteinElement expression
2015
Time course of cardiac inflammation during nitric oxide synthase inhibition in SHR: impact of prior transient ACE inhibition
Biwer L, D'souza K, Abidali A, Tu D, Siniard A, DeBoth M, Huentelman M, Hale T. Time course of cardiac inflammation during nitric oxide synthase inhibition in SHR: impact of prior transient ACE inhibition. Hypertension Research 2015, 39: 8-18. PMID: 26490086, DOI: 10.1038/hr.2015.107.Peer-Reviewed Original ResearchConceptsTransient ACE inhibitionNAME treatmentPulse pressureNOS inhibitionACE inhibitionCardiac remodelingInterleukin-6Nitric oxide synthase inhibitionCytokine/chemokine levelsNitric oxide synthase inhibitorMonocyte chemoattractant protein-1Adult male SHRChemokine release profileOxide synthase inhibitionOxide synthase inhibitorChemoattractant protein-1Arginine methyl esterPathological cardiac remodelingChemokine levelsMale SHRCardiac inflammationArterial pressureBlood pressureHypertensive ratsIL-10Persistent change in cardiac fibroblast physiology after transient ACE inhibition
D'Souza K, Biwer L, Madhavpeddi L, Ramaiah P, Shahid W, Hale T. Persistent change in cardiac fibroblast physiology after transient ACE inhibition. AJP Heart And Circulatory Physiology 2015, 309: h1346-h1353. PMID: 26371174, DOI: 10.1152/ajpheart.00615.2015.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin-Converting Enzyme InhibitorsAnimalsCardiomyopathiesCell ProliferationCells, CulturedChemokine CCL2Collagen Type IDisease Models, AnimalEnalaprilFibroblastsFibrosisGranulocyte-Macrophage Colony-Stimulating FactorHeart VentriclesHypertensionInflammation MediatorsMaleNG-Nitroarginine Methyl EsterNitric Oxide SynthasePhenotypeRats, Inbred SHRTime FactorsConceptsTransient ACE inhibitionACE inhibitionFibroblast physiologyArginine methyl ester treatmentCardiac fibroblastsAngiotensin-converting enzyme inhibitionPersistent changesMethyl ester treatmentChemoattractant protein-1Granulocyte macrophage-colony stimulating factorArginine methyl esterMacrophage-colony stimulating factorMacrophage-recruiting chemokinesCardiac fibroblast phenotypeRole of fibroblastsUntreated SHRHypertensive ratsNOS inhibitionWashout periodACE inhibitorsCardioprotective effectsChemokine releaseMyocardial injuryCardiac fibrosisNOS inhibitor
2014
Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall
Billaud M, Lohman A, Johnstone S, Biwer L, Mutchler S, Isakson B. Regulation of Cellular Communication by Signaling Microdomains in the Blood Vessel Wall. Pharmacological Reviews 2014, 66: 513-569. PMID: 24671377, PMCID: PMC3973613, DOI: 10.1124/pr.112.007351.Peer-Reviewed Original ResearchConceptsCellular communicationAccumulation of proteinsMechanism of exocytosisSignaling microdomainProper vascular functionPlasma membraneBlood vessel wallCell typesIon channelsMicrodomainsGap junctionsOxygen speciesPotassium channelsVon Willebrand factorPlethora of meansRegulationSpecific regionsEssential componentVessel wall functionWillebrand factorParacrine releaseImportant roleVessel wallExocytosisEndothelium-derived hyperpolarization
2012
Protection against L‐NAME‐induced reduction in cardiac output persists even after cessation of angiotensin‐converting enzyme inhibitor treatment
Biwer L, Broderick T, Xu H, Carroll C, Hale T. Protection against L‐NAME‐induced reduction in cardiac output persists even after cessation of angiotensin‐converting enzyme inhibitor treatment. Acta Physiologica 2012, 207: 156-165. PMID: 22834875, DOI: 10.1111/j.1748-1716.2012.02474.x.Peer-Reviewed Original ResearchConceptsL-NAMEMyocardial injuryCardiac functionEnalapril treatmentACE inhibitionCardiac outputL ratsL-NAME-induced reductionNitric oxide synthase inhibitorShort-term angiotensinTransient ACE inhibitionEnzyme inhibitor treatmentHeart failure treatmentCessation of treatmentOxide synthase inhibitorArginine methyl esterEosin-stained sectionsArterial pressureHypertensive ratsCardiac changesCardiac dysfunctionWashout periodCoronary flowMyocardial infarctionFailure treatment