title: Interference with peroxisome proliferator-activated receptor-γ in vascular smooth muscle causes baroreflex impairment and autonomic dysfunction.
abstract: S-P467L mice expressing dominant negative peroxisome proliferator-activated receptor-γ selectively in vascular smooth muscle exhibit impaired vasodilation, augmented vasoconstriction, hypertension, and tachycardia. We hypothesized that tachycardia in S-P467L mice is a result of baroreflex dysfunction. S-P467L mice displayed increased sympathetic traffic to the heart and decreased baroreflex gain and effectiveness. Carotid arteries exhibited inward remodeling but no changes in distensibility or stress/strain. Aortic depressor nerve activity in response to increased arterial pressure was blunted in S-P467L mice. However, the arterial pressure and heart rate responses to aortic depressor nerve stimulation were unaltered in S-P467L mice, suggesting that the central and efferent limbs of the baroreflex arc remain intact. There was no transgene expression in nodose ganglion and no change in expression of the acid-sensing ion channel-2 or -3 in nodose ganglion. There was a trend toward decreased expression of transient receptor potential vanilloid-1 receptor mRNA in nodose ganglion, but no difference in the immunochemical staining of transient receptor potential vanilloid-1 receptor in the termination area of the left aortic depressor nerve in S-P467L mice. Although there was no difference in the maximal calcium response to capsaicin in cultured nodose neurons from S-P467L mice, there was decreased desensitization of transient receptor potential vanilloid-1 receptor channels. In conclusion, S-P467L mice exhibit baroreflex dysfunction because of a defect in the afferent limb of the baroreflex arc caused by impaired vascular function, altered vascular structure, or compromised neurovascular coupling. These findings implicate vascular smooth muscle peroxisome proliferator activated receptor-γ as a critical determinant of neurovascular signaling.
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Giulianna R
authors.initials: GR
authors.lastname: Borges
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Donald A
authors.initials: DA
authors.lastname: Morgan
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Pimonrat
authors.initials: P
authors.lastname: Ketsawatsomkron
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Mickle
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Thompson
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Martin D
authors.initials: MD
authors.lastname: Cassell
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Durga P
authors.initials: DP
authors.lastname: Mohapatra
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City.
authors.forename: Kamal
authors.initials: K
authors.lastname: Rahmouni
authors.affiliation: From the Department of Pharmacology (G.R.B., D.A.M., P.K., A.D.M., D.P.M., K.R., C.D.S.), Department of Anatomy and Cell Biology (A.P.T., M.D.C.), and Center on the Functional Genomics of Hypertension (K.R., C.D.S.), Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City. curt-sigmund@uiowa.edu.
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000818:Animals; D001341:Autonomic Nervous System / Q000503:physiopathology; D001342:Autonomic Nervous System Diseases / Q000503:physiopathology*; D017704:Baroreflex / Q000502:physiology*; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006339:Heart Rate / Q000502:physiology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000503:physiopathology*; D009620:Nodose Ganglion / Q000187:drug effects / Q000502:physiology; D047495:PPAR gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013610:Tachycardia / Q000503:physiopathology*
chemical_list: D047495:PPAR gamma; D002211:Capsaicin; D002118:Calcium
keywords: baroreflex; blood pressure; heart rate; muscle, smooth, vascular; peroxisome proliferator-activated receptors; sympathetic nervous system