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Functions of prostacyclin in vascular and uterine smooth muscle.

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Call No.	QP752.P69 F48 2009
Author	Fetalvero, Kristina M.
Title	Functions of prostacyclin in vascular and uterine smooth muscle.
Date	2009
Abstract	Prostacyclin (PGI2) is a major product of COX-2 derived arachidonic acid metabolism in the endothelium and uterine myometrium. Evidence indicates that PGI 2 protects against development and progression of vascular disease. While it has been known for some time that PGI 2 signals through the prostacyclin receptor (IP), a G-protein coupled receptor (GPCR), mechanisms by which its actions protect the vasculature are only beginning to be appreciated. Understanding the role of PGI 2 as a mediator of vascular smooth muscle cell (VSMC) phenotype is relevant, as VSMC are highly plastic cells that become de-differentiated in response to changes in local environmental cues, ultimately contributing to the development of vascular disease. Our data demonstrate that PGI 2 induced cAMP/PKA signaling is involved in phenotypic modulation of VSMC and that this is a likely mechanism by which PGI 2 is cardioprotective. In contrast, the role of PGI 2 in parturition has remained elusive, as PGI 2 is a known smooth muscle relaxant; however, PGI 2 levels increase as labor approaches, a time when the main function of the myometrium is to contract. As we demonstrated that PGI 2 promoted a contractile phenotype in VSMC by increasing contractile proteins, we hypothesized that PGI 2 signaling might also promote a switch from the pregnant quiescent myometrium to an activated state during labor. We report that incubation of human pregnant myometrial tissue with iloprost enhances tissue responsiveness to the potent SM contractant oxytocin. This appears to be a result of an induction of multiple procontractile factors including the oxytocin receptor, connexin 43, and smooth muscle myosin heavy chain (SM-MHC). PGI 2 signaling additionally increases COX-2 expression, which results in a positive feed-forward mechanism leading to increased synthesis of PGF 2α. Importantly, PKA was necessary for these effects, which is paradoxical to previous reports that cAMP/PKA signaling maintains uterine quiescence. We additionally identified a downstream target of PGI 2 signaling, the transcription factor GATA-6, which has been reported to be critical in modulating VSMC phenotype, and, as we show, is also necessary for iloprost induction of COX-2 and SM-MHC in uSMCs. Our data suggest that activation of cAMP/PKA signaling in response to iloprost stimulates changes in both vascular and myometrial smooth muscle cells that promotes a contractile state.
Description	xiii, 260 leaves : ill. 28 cm.
Format	application/pdf
Advisor	Martin, Kathleen A., Robbins, David J., Tevosian, Sergei G., Young, Roger C., Hwa, John
Subject	Prostacyclin -- Physiological effect. Vascular smooth muscle. Vascular endothelium -- Physiology. Myometrium -- Physiology. Cardiovascular system -- Diseases. Cellular signal transduction.
College	Dartmouth Medical School -- Department of Pharmacology and Toxicology.
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Copyright	All rights reserved. No part of this book may be reproduced in any form by any electronic or mechanical means without permission in writing from the author.
DOI	http://dx.doi.org/10.1349/ddlp.258

Title	Page 1
Format	application/pdf
Issuing Body	Dartmouth Dissertations are made available through the Dartmouth Digital Library.
Degree	Thesis (Ph.D.)--Dartmouth College.
Full Text	Functions of Prostacyclin in Vascular and Uterine Smooth Muscle A Thesis Submitted to the Faculty in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Pharmacology and Toxicology by Kristina M. Fetalvero DARTMOUTH COLLEGE Hanover, New Hampshire January 2, 2009 Examining Committee: ___________________________ (chair) Kathleen A. Martin, Ph.D. ___________________________ David J. Robbins, Ph.D. ___________________________ Sergei G. Tevosian, Ph.D. ___________________________ Roger C. Young, M.D., Ph.D. ___________________________ ___________________________ Brian W. Pogue, Ph.D. John Hwa, M.D., Ph.D. Dean of Graduate Studies

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