Document Detail


Uterine artery myosin phosphatase isoform switching and increased sensitivity to SNP in a rat L-NAME model of hypertension of pregnancy.
MedLine Citation:
PMID:  18094148     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dramatic and vascular bed-specific hemodynamic changes occur in pregnancy and hypertension of pregnancy (HtP). Because myosin phosphatase (MP) is the primary effector of smooth muscle relaxation and a key target of signaling pathways that regulate vascular tone, we hypothesized that MP expression would be altered in these conditions. The abundance of the targeting/regulatory subunit of MP (MYPT1) mRNA and protein was increased 1.7- to 2.0-fold specifically in the uterine arteries (UAs) of late-pregnant rats without isoform switching. In a model of HtP in which nitric oxide (NO) synthesis is blocked by the chronic administration of N(omega)-nitro-L-arginine methyl ester, MYPT1 was downregulated and switched to the splice variant isoform that codes for the COOH-terminal leucine zipper motif. This was associated with increased sensitivity of the main UA and its subbranches to the vasorelaxant effects of the NO donor drug sodium nitroprusside. This difference was abolished by pretreatment with the phosphatase inhibitor tautomycetin. The sensitivity of relaxation to the NO second messenger cGMP was also increased under calcium-clamp conditions in permeabilized UAs, indicating heightened activation of MP. The changes in MP expression in HtP were largely prevented by treatment with the antihypertensive medicine hydralazine. We propose that MYPT1 isoform switching is an adaptive response to reduce vascular resistance and maintain uterine blood flow in the setting of hypertension-triggered inward remodeling of the UAs in hypertension of pregnancy.
Authors:
Yuan Lu; Haiying Zhang; Natalia Gokina; Maurizio Mandala; Osamu Sato; Mitsuo Ikebe; George Osol; Steven A Fisher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2007-12-19
Journal Detail:
Title:  American journal of physiology. Cell physiology     Volume:  294     ISSN:  0363-6143     ISO Abbreviation:  Am. J. Physiol., Cell Physiol.     Publication Date:  2008 Feb 
Date Detail:
Created Date:  2008-02-15     Completed Date:  2008-04-17     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  100901225     Medline TA:  Am J Physiol Cell Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  C564-71     Citation Subset:  IM    
Affiliation:
Department of Medicine, Case Western Reserve School of Medicine, Cleveland, OH 44106-7290, USA.
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MeSH Terms
Descriptor/Qualifier:
Alternative Splicing / drug effects,  genetics
Animals
Arteries / enzymology*,  physiopathology
Cyclic GMP / metabolism
Disease Models, Animal
Down-Regulation / drug effects,  genetics
Enzyme Inhibitors / pharmacology
Female
Furans / pharmacology
Hypertension, Pregnancy-Induced / enzymology*,  physiopathology
Lipids / pharmacology
Muscle, Smooth, Vascular / enzymology*,  physiopathology
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide / metabolism*
Nitric Oxide Donors / pharmacology
Nitric Oxide Synthase / antagonists & inhibitors,  metabolism
Nitroprusside / pharmacology
Pregnancy
Protein Phosphatase 1 / antagonists & inhibitors,  genetics,  metabolism*
RNA, Messenger / drug effects,  metabolism
Rats
Rats, Sprague-Dawley
Regional Blood Flow / drug effects,  genetics
Uterus / blood supply*,  physiopathology
Grant Support
ID/Acronym/Agency:
HL-073050/HL/NHLBI NIH HHS; HL-073895/HL/NHLBI NIH HHS; HL-66171/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Furans; 0/Lipids; 0/Nitric Oxide Donors; 0/RNA, Messenger; 10102-43-9/Nitric Oxide; 119757-73-2/tautomycetin; 15078-28-1/Nitroprusside; 50903-99-6/NG-Nitroarginine Methyl Ester; 7665-99-8/Cyclic GMP; EC 1.14.13.39/Nitric Oxide Synthase; EC 3.1.3.16/Ppp1r12a protein, rat; EC 3.1.3.16/Protein Phosphatase 1

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