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VASCULAR BIOLOGY

Uterine artery myosin phosphatase isoform switching and increased sensitivity to SNP in a rat L-NAME model of hypertension of pregnancy

¹Department of Medicine (Cardiology), Case Western Reserve School of Medicine, Cleveland, Ohio; ²Department of Obstetrics and Gynecology, College of Medicine, University of Vermont, Burlington, Vermont; ³Department of Cell Biology, University of Calabria, Cosenza, Italy; and ⁴Department of Physiology, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 20 July 2007 ; accepted in final form 7 January 2008

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-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.

smooth muscle; gene expression; guanosine 3',5'-cyclic monophosphate; contractility; signaling; N-nitro-L-arginine methyl ester; sodium nitroprusside