Uterine artery myosin phosphatase isoform switching and increased sensitivity to SNP in a rat L-NAME model of hypertension of pregnancy.
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.
Lu
Yuan
Y
Department of Medicine, Case Western Reserve School of Medicine, Cleveland, OH 44106-7290, USA.
Zhang
Haiying
H
Gokina
Natalia
N
Mandala
Maurizio
M
Sato
Osamu
O
Ikebe
Mitsuo
M
Osol
George
G
Fisher
Steven A
SA
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001158:Arteries / Q000201:enzymology* / Q000503:physiopathology; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology; D046110:Hypertension, Pregnancy-Induced / Q000201:enzymology* / Q000503:physiopathology; D008055:Lipids / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000201:enzymology* / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D011247:Pregnancy; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012039:Regional Blood Flow / Q000187:drug effects / Q000235:genetics; D014599:Uterus / Q000098:blood supply* / Q000503:physiopathology
D004791:Enzyme Inhibitors; D005663:Furans; D008055:Lipids; D020030:Nitric Oxide Donors; D012333:RNA, Messenger; C058744:tautomycetin; D009599:Nitroprusside; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; C499850:Ppp1r12a protein, rat; D054645:Protein Phosphatase 1; D006152:Cyclic GMP; D019331:NG-Nitroarginine Methyl Ester