RATIONALE: Activation of peroxisome proliferator-activated receptor-γ (PPARγ) by thiazolidinediones lowers blood pressure, whereas PPARγ mutations cause hypertension. Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear. OBJECTIVE: To identify PPARγ mechanisms and transcriptional targets in vascular smooth muscle and their role in regulating resistance artery tone. METHODS AND RESULTS: We studied mesenteric artery (MA) from transgenic mice expressing dominant-negative (DN) mutant PPARγ driven by a smooth muscle cell-specific promoter. MA from transgenic mice exhibited a robust increase in myogenic tone. Patch clamp analysis revealed a reduced large conductance Ca(2+)-activated K(+) (BKCa) current in freshly dissociated smooth muscle cell from transgenic MA. Inhibition of protein kinase C corrected both enhanced myogenic constriction and impaired the large conductance Ca(2+)-activated K(+) channel function. Gene expression profiling revealed a marked loss of the regulator of G protein signaling 5 (RGS5) mRNA in transgenic MA, which was accompanied by a substantial increase in angiotensin II-induced constriction in MA. Small interfering RNA targeting RGS5 caused augmented myogenic tone in intact mesenteric arteries and increased activation of protein kinase C in smooth muscle cell cultures. PPARγ and PPARδ each bind to a PPAR response element close to the RGS5 promoter. RGS5 expression in nontransgenic MA was induced after activation of either PPARγ or PPARδ, an effect that was markedly blunted by DN PPARγ. CONCLUSIONS: We conclude that RGS5 in smooth muscle is a PPARγ and PPARδ target, which when activated blunts angiotensin II-mediated activation of protein kinase C, and preserves the large conductance Ca(2+)-activated K(+) channel activity, thus providing tight control of myogenic tone in the microcirculation.
RATIONALE: Activation of peroxisome proliferator-activated receptor-γ (PPARγ) by thiazolidinediones lowers blood pressure, whereas PPARγ mutations cause hypertension. Previous studies suggest these effects may be mediated through the vasculature, but the underlying mechanisms remain unclear. OBJECTIVE: To identify PPARγ mechanisms and transcriptional targets in vascular smooth muscle and their role in regulating resistance artery tone. METHODS AND RESULTS: We studied mesenteric artery (MA) from transgenic mice expressing dominant-negative (DN) mutant PPARγ driven by a smooth muscle cell-specific promoter. MA from transgenic mice exhibited a robust increase in myogenic tone. Patch clamp analysis revealed a reduced large conductance Ca(2+)-activated K(+) (BKCa) current in freshly dissociated smooth muscle cell from transgenic MA. Inhibition of protein kinase C corrected both enhanced myogenic constriction and impaired the large conductance Ca(2+)-activated K(+) channel function. Gene expression profiling revealed a marked loss of the regulator of G protein signaling 5 (RGS5) mRNA in transgenic MA, which was accompanied by a substantial increase in angiotensin II-induced constriction in MA. Small interfering RNA targeting RGS5 caused augmented myogenic tone in intact mesenteric arteries and increased activation of protein kinase C in smooth muscle cell cultures. PPARγ and PPARδ each bind to a PPAR response element close to the RGS5 promoter. RGS5 expression in nontransgenic MA was induced after activation of either PPARγ or PPARδ, an effect that was markedly blunted by DN PPARγ. CONCLUSIONS: We conclude that RGS5 in smooth muscle is a PPARγ and PPARδ target, which when activated blunts angiotensin II-mediated activation of protein kinase C, and preserves the large conductance Ca(2+)-activated K(+) channel activity, thus providing tight control of myogenic tone in the microcirculation.
Authors: I Barroso; M Gurnell; V E Crowley; M Agostini; J W Schwabe; M A Soos; G L Maslen; T D Williams; H Lewis; A J Schafer; V K Chatterjee; S O'Rahilly Journal: Nature Date: 1999 Dec 23-30 Impact factor: 49.962
Authors: Xiao-Bo Zhou; Iris Wulfsen; Emine Utku; Ulrike Sausbier; Matthias Sausbier; Thomas Wieland; Peter Ruth; Michael Korth Journal: Proc Natl Acad Sci U S A Date: 2010-04-12 Impact factor: 11.205
Authors: R K Semple; A Meirhaeghe; A J Vidal-Puig; J W R Schwabe; D Wiggins; G F Gibbons; M Gurnell; V K K Chatterjee; S O'Rahilly Journal: Endocrinology Date: 2005-01-20 Impact factor: 4.736
Authors: Torben Helledie; Lars Grøntved; Søren S Jensen; Pia Kiilerich; Luc Rietveld; Tatjana Albrektsen; Maria S Boysen; Jane Nøhr; Leif K Larsen; Jan Fleckner; Hendrik G Stunnenberg; Karsten Kristiansen; Susanne Mandrup Journal: J Biol Chem Date: 2002-05-15 Impact factor: 5.157
Authors: Yen-Pei Christy Chang; Xin Liu; James Dae Ok Kim; Morna A Ikeda; Marnie R Layton; Alan B Weder; Richard S Cooper; Sharon L R Kardia; D C Rao; Steve C Hunt; Amy Luke; Eric Boerwinkle; Aravinda Chakravarti Journal: Am J Hum Genet Date: 2006-12-20 Impact factor: 11.025
Authors: María José Zarzuelo; Rosario Jiménez; Pilar Galindo; Manuel Sánchez; Ana Nieto; Miguel Romero; Ana María Quintela; Rocío López-Sepúlveda; Manuel Gómez-Guzmán; Elvira Bailón; Isabel Rodríguez-Gómez; Antonio Zarzuelo; Julio Gálvez; Juan Tamargo; Francisco Pérez-Vizcaíno; Juan Duarte Journal: Hypertension Date: 2011-08-08 Impact factor: 9.897
Authors: Yasunori Takata; Joey Liu; Fen Yin; Alan R Collins; Christopher J Lyon; Chih-Hao Lee; Annette R Atkins; Michael Downes; Grant D Barish; Ronald M Evans; Willa A Hsueh; Rajendra K Tangirala Journal: Proc Natl Acad Sci U S A Date: 2008-03-12 Impact factor: 12.779
Authors: Kristoffer Rosenstand; Kenneth Andersen; Rasmus Terp; Peter Gennemark; Ditte Gry Ellman; Anna Reznichenko; Kate Lykke Lambertsen; Paul M Vanhoutte; Pernille B L Hansen; Per Svenningsen Journal: J Physiol Biochem Date: 2020-02-03 Impact factor: 4.158
Authors: Larry N Agbor; Anand R Nair; Jing Wu; Ko-Ting Lu; Deborah R Davis; Henry L Keen; Frederick W Quelle; James A McCormick; Jeffrey D Singer; Curt D Sigmund Journal: JCI Insight Date: 2019-06-11
Authors: Pimonrat Ketsawatsomkron; Henry L Keen; Deborah R Davis; Ko-Ting Lu; Madeliene Stump; T Michael De Silva; Aline M Hilzendeger; Justin L Grobe; Frank M Faraci; Curt D Sigmund Journal: Hypertension Date: 2015-11-23 Impact factor: 10.190