Journal article
Genetic Interference With Peroxisome Proliferator-Activated Receptor gamma in Smooth Muscle Enhances Myogenic Tone in the Cerebrovasculature via A Rho Kinase-Dependent Mechanism
Hypertension (Dallas, Tex. 1979), Vol.65(2), pp.345-U234
02/01/2015
DOI: 10.1161/HYPERTENSIONAHA.114.04541
PMCID: PMC4289099
PMID: 25385762
Abstract
Myogenic responses by resistance vessels are a key component of autoregulation in brain, thus playing a crucial role in regulating cerebral blood flow and protecting the blood-brain barrier against potentially detrimental elevations in blood pressure. Although cerebrovascular disease is often accompanied by alterations in myogenic responses, mechanisms that control these changes are poorly understood. Peroxisome proliferator-activated receptor gamma has emerged as a regulator of vascular tone. We hypothesized that interference with peroxisome proliferator-activated receptor gamma in smooth muscle would augment myogenic responses in cerebral arteries. We studied transgenic mice expressing a dominant-negative mutation in peroxisome proliferator-activated receptor gamma selectively in smooth muscle (S-P467L) and nontransgenic littermates. Myogenic tone in middle cerebral arteries from S-P467L was elevated 3-fold when compared with nontransgenic littermates. Rho kinase is thought to play a major role in cerebrovascular disease. The Rho kinase inhibitor, Y-27632, abolished augmented myogenic tone in middle cerebral arteries from S-P467L mice. CN-03, which modifies RhoA making it constitutively active, elevated myogenic tone to approximate to 60% in both strains, via a Y-27632-dependent mechanism. Large conductance Ca2+-activated K+ channels (BKCa) modulate myogenic tone. Inhibitors of BKCa caused greater constriction in middle cerebral arteries from nontransgenic littermates when compared with S-P467L. Expression of RhoA or Rho kinase-I/II protein was similar in cerebral arteries from S-P467L mice. Overall, the data suggest that peroxisome proliferator-activated receptor gamma in smooth muscle normally inhibits Rho kinase and promotes BKCa function, thus influencing myogenic tone in resistance arteries in brain. These findings have implications for mechanisms that underlie large- and small-vessel disease in brain, as well as regulation of cerebral blood flow.
Details
- Title: Subtitle
- Genetic Interference With Peroxisome Proliferator-Activated Receptor gamma in Smooth Muscle Enhances Myogenic Tone in the Cerebrovasculature via A Rho Kinase-Dependent Mechanism
- Creators
- T. Michael De Silva - Roy J. and Lucille A. Carver College of MedicinePimonrat Ketsawatsomkron - Roy J. and Lucille A. Carver College of MedicineChristopher Pelham - Roy J. and Lucille A. Carver College of MedicineCurt D. Sigmund - Roy J. and Lucille A. Carver College of MedicineFrank M. Faraci - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Hypertension (Dallas, Tex. 1979), Vol.65(2), pp.345-U234
- DOI
- 10.1161/HYPERTENSIONAHA.114.04541
- PMID
- 25385762
- PMCID
- PMC4289099
- NLM abbreviation
- Hypertension
- ISSN
- 0194-911X
- eISSN
- 1524-4563
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 19
- Grant note
- Fondation Leducq (a Transatlantic Network of Excellence); Leducq Foundation Roy J. Carver Trust BX001399 / Department of Veterans Affairs; US Department of Veterans Affairs 12POST9150027; 11POST5720021 / American Heart Association 1053786 / National Health and Medical Research Council of Australia; National Health and Medical Research Council (NHMRC) of Australia P01HL062984; P01HL084207; R01HL048058; R01HL113863; R37HL048058; R01HL061446 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI) HL-62984; HL-113863; HL-048058; HL-061446 / National Institute of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA I01BX001399 / Veterans Affairs; US Department of Veterans Affairs
- Language
- English
- Date published
- 02/01/2015
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Neuroscience and Pharmacology; Internal Medicine
- Record Identifier
- 9984303742502771
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