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ABSTRACT: In the classical pathway, the opposing activities of guanylyl cyclases (GC) and phosphodiesterases (PDE), and the effect of the cGMP-dependent protein kinase (cGK) on its targets, determine the biological responses to NO signaling. Here we tested the hypothesis that vascular dysfunction may be due to altered expression and activity of these effectors of NO signaling. Every other set of rat second order mesenteric resistance arteries (MA) were ligated, resulting in chronic low flow (LF) in the upstream MA1 and high flow (HF) in the adjacent MA1 without tissue ischemia. eNOS and iNOS were up-regulated in HF and LF MA1, respectively, in the sub-acute phase (four days) of vascular remodeling. The Day4 HF/LF MA1s were under increased control of NO as indicated by reduced sensitivity to the vasoconstrictor phenylephrine and its normalization with the NOS antagonist L-NAME. PDE5 mRNA and protein were also significantly up-regulated in the HF/LF MA1 with no change in sGC or PKG1, an effect that was dependent upon NO synthesis. The PDE5 inhibitor Sildenafil was several-fold more powerful in relaxing the HF/LF MA1s, and pre-treatment with Sildenafil uncovered an increased responsiveness of HF/LF MA1s to the NO donor DEA/NO. We conclude that induction of PDE5 de-sensitizes this systemic resistance artery to sustained NO signaling under chronic HF/LF. Treatment with PDE5 antagonists, in contrast to NO donors, may more specifically and effectively increase blood flow to chronically hypo-perfused tissues.
Journal of Molecular and Cellular Cardiology 05/2009; 47(1):57-65. · 5.17 Impact Factor
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ABSTRACT: 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.
AJP Cell Physiology 03/2008; 294(2):C564-71. · 3.54 Impact Factor
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ABSTRACT: Myosin phosphatase is the primary effector of smooth muscle relaxation and a target of signaling pathways that regulate vascular tone. The mesenteric small resistance artery and large vessel smooth muscle express distinct isoforms of the myosin phosphatase targeting subunit (MYPT1), and the isoforms in the small resistance artery switch in a disease model of altered blood flow. We thus hypothesized that small resistance artery smooth muscle phenotype is responsive to altered blood flow. To test this hypothesis alternating pairs of rat second order mesenteric arteries were ligated so that the upstream first order mesenteric artery (MA1) is under chronic low flow and the adjacent first order mesenteric artery under chronic high flow. The initial response was similar in high flow and low flow MA1, and included rapid reduction in MYPT1 and switch to the 3' alternative exon skipped/leucine zipper positive MYPT1 isoform. Between 14 to 28 days, MYPT1 abundance was restored along with reversion to the MYPT1 leucine zipper(-) isoform under chronic high flow. In contrast, under continued low flow, there was further switching to the MYPT1 leucine zipper(+) isoform. As would be predicted based on the switch to the MYPT1 leucine zipper(+) isoform, the sensitivity for relaxation to the NO donor SIN-1 and to cGMP was increased in the Day28 low flow first order mesenteric artery. We conclude that pulsatile blood flow conditions the phasic program of gene expression in the small resistance artery smooth muscle. The loss of this conditioning effect significantly increases the sensitivity to vasodilator signals in the setting of chronically reduced blood flow.
Circulation Research 04/2007; 100(5):730-7. · 9.49 Impact Factor
