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 damageA Novel Dual-Function Nitric Oxide Donor Therapy for Preeclampsia—A Proof-of-Principle Study in a Murine Model
Pintye D, Sziva R, Biwer L, Karreci E, Jacas S, Mastyugin M, Török M, Young B, Jagtap P, Southan G, Jaffe I, Zsengellér Z. A Novel Dual-Function Nitric Oxide Donor Therapy for Preeclampsia—A Proof-of-Principle Study in a Murine Model. Antioxidants 2023, 12: 2036. PMID: 38136156, PMCID: PMC10741224, DOI: 10.3390/antiox12122036.Peer-Reviewed Original ResearchBlood pressureOxidative stressNitric oxide donor therapyPlasma cystatin C.Plasma nitrate levelsHealthy female miceModel of preeclampsiaNitric oxide bioavailabilityEx vivo treatmentPotential therapeutic effectsReduced oxidative stressNovel therapeutic agentsDays of treatmentAnti-angiogenic responseDonor therapyPlacental damageReduced hypertensionHypertensive disordersSubstantial morbidityFetal pathophysiologyResistance vesselsGlomerular endotheliosisPE symptomsVascular disordersFemale miceMineralocorticoid 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
2024
Mineralocorticoid Receptors in Vascular Smooth Muscle: Blood Pressure and Beyond
Camarda N, Ibarrola J, Biwer L, Jaffe I. Mineralocorticoid Receptors in Vascular Smooth Muscle: Blood Pressure and Beyond. Hypertension 2024, 81: 1008-1020. PMID: 38426347, PMCID: PMC11023801, DOI: 10.1161/hypertensionaha.123.21358.Peer-Reviewed Original ResearchSmooth muscle cellsSMC-MRMineralocorticoid receptorBlood pressurePulmonary hypertensionHeart failureVascular calcificationAngiotensin II type 1 receptorRegulation of vasomotor functionVascular smooth muscleMR knockout miceType 1 receptorAortic valve diseaseSystemic blood pressureSMC proliferationConnective tissue growth factorMatrix metallopeptidase-2Heart valve dysfunctionDiverse cardiovascular disordersResponse to hypertensionTissue growth factorIn vitro studiesIn vivo findingsMyogenic toneValve dysfunction
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
2020
Myoendothelial Junctions of Mature Coronary Vessels Express Notch Signaling Proteins
McCallinhart P, Biwer L, Clark O, Isakson B, Lilly B, Trask A. Myoendothelial Junctions of Mature Coronary Vessels Express Notch Signaling Proteins. Frontiers In Physiology 2020, 11: 29. PMID: 32116749, PMCID: PMC7010921, DOI: 10.3389/fphys.2020.00029.Peer-Reviewed Original ResearchInternal elastic laminaMyoendothelial junctionsCoronary circulationCoronary ECsBlood vesselsIntact blood vesselsNotch signalingSmooth muscleMature blood vesselsNotch3 expressionNotch inhibitorsNotch receptorsElastic laminaTranswell insertsCell phenotypeNormal vasculogenesisVSMCsCell contactReceptorsCritical determinantCell-cell contactSignalingVesselsNotch activityCritical sites
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
2017
A Cell Culture Model of Resistance Arteries.
Biwer L, Lechauve C, Vanhoose S, Weiss M, Isakson B. A Cell Culture Model of Resistance Arteries. Journal Of Visualized Experiments 2017 PMID: 28930992, PMCID: PMC5752193, DOI: 10.3791/55992.Peer-Reviewed Original ResearchConceptsCell culture modelCell typesMyoendothelial junctionsEndothelial cell polarizationPlating of cellsIntact cell layerDifferent cell typesSignaling microdomainCulture modelSpecific proteinsCell polarizationPhysiological relevanceActivity assaysProtein isolationSmooth muscle cellsVascular cellsMuscle cellsImmunofluorescent analysisIntact resistance arteriesProteinCellsMuscle fractionsIsolationCell layerVCCCLoss of endothelial Fto is protective against metabolic disease
Krüger N, Biwer L, Good M, Rüther U, Isakson B. Loss of endothelial Fto is protective against metabolic disease. The FASEB Journal 2017, 31 DOI: 10.1096/fasebj.31.1_supplement.1015.15.Peer-Reviewed Original ResearchHigh-fat dietObesity-induced metabolic changesHFD-fed miceMyogenic toneBlood pressureNormal chowMesenteric arteryResistance arteriesEndothelial cellsMetabolic changesNC-fed miceObesity-induced hypertensionSerum lipid levelsOrder mesenteric arteriesSerum lipid analysisFto-deficient miceVascular healthVascular levelVascular toneInsulin resistanceInsulin toleranceFat dietPathophysiological changesDeficient miceFat massCalreticulin localized to the myoendothelial junction mediates heterocellular communication in resistance arteries
Biwer L, Good M, Hong K, Patel R, Agrawal N, Looft‐Wilson R, Sonkusare S, Isakson B. Calreticulin localized to the myoendothelial junction mediates heterocellular communication in resistance arteries. The FASEB Journal 2017, 31 DOI: 10.1096/fasebj.31.1_supplement.681.12.Peer-Reviewed Original ResearchEndoplasmic reticulumHeterocellular communicationSmooth muscle cellsER retention signal KDELMyoendothelial junctionsExpression of ERCa 2Proteomic screenConditional knockout micePresence of calreticulinSecond messengerCell extensionsER-TrackerBidirectional signalingBinding proteinCalcium binding proteinSignificant enrichmentCalreticulinER calciumAgonist stimulationCytoplasmic contactMuscle cellsProteinKnockout miceSmooth muscle agonists
2016
Two functionally distinct pools of eNOS in endothelium are facilitated by myoendothelial junction lipid composition
Biwer L, Taddeo E, Kenwood B, Hoehn K, Straub A, Isakson B. Two functionally distinct pools of eNOS in endothelium are facilitated by myoendothelial junction lipid composition. Biochimica Et Biophysica Acta 2016, 1861: 671-679. PMID: 27106139, PMCID: PMC4869716, DOI: 10.1016/j.bbalip.2016.04.014.Peer-Reviewed Original ResearchMeSH KeywordsBiological TransportBradykininCalciumCalcium SignalingCell CommunicationCoculture TechniquesCyclic GMPDiglyceridesEgtazic AcidEndoplasmic ReticulumEndothelial CellsGap JunctionsGene Expression RegulationHumansInositol 1,4,5-TrisphosphateMacrocyclic CompoundsMyocytes, Smooth MuscleNitric Oxide Synthase Type IIIOxazolesPhenylephrinePhosphatidylserinesPhosphorylationPrimary Cell CultureProtein Kinase CProtein Kinase InhibitorsThapsigarginEndoplasmic 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