Serum Starvation and Growth Factor Receptor Expression in Vascular Smooth Muscle Cells

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Abstract

Background: Smooth muscle cell (SMC) proliferation in atherosclerosis is regulated through the interaction of growth factors like platelet-derived growth factor-BB (PDGF-BB) and insulin-like growth factor-1 (IGF-1) and their receptors (R). We hypothesized that serum starvation of SMCs may affect PDGFβ-R and IGF-1-R expression and, consequently, the effect of their cognate ligands on SMC survival/proliferation. Methods and Results: Serum starvation significantly increases PDGFβ-R but not IGF-1-R mRNA and protein expression in SMCs. PDGF-BB stimulates cell survival but not proliferation in serum-starved SMCs of the synthetic phenotype, whereas SMCs of the contractile phenotype respond to PDGF-BB by a significant increase in proliferation. Immunohistochemical analysis of coronary atherosclerotic lesions reveals PDGFβ-R expression in SMCs in the lamina fibromuscularis, but not in the media and in healthy parts of the arterial wall. No such differential expression was observed for IGF-1-R. Conclusions: Differential regulation of PDGFβ-R and IGF-1-R expression by serum starvation might represent a mechanism for the control of SMC survival/proliferation in atherogenesis and restenosis. The distribution of PDGFβ-Rs and IGF-1-Rs in atherosclerotic lesions may indicate an effect of serum starvation on SMCs in the arterial wall.

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High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

N Cary, Roger P Weissberg, J. Metcalfe … (1994)

Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. However, little is known about the mechanisms which regulate the calcification process. Using in situ hybridization and immunohistochemistry we show that two bone-associated proteins, osteopontin (OP) and matrix Gla protein (MGP), are highly expressed in human atheromatous plaques. High levels of OP mRNA and protein were found in association with necrotic lipid cores and areas of calcification. The predominant cell type in these areas was the macrophage-derived foam cell, although some smooth muscle cells could also be identified. MGP was expressed uniformly by smooth muscle cells in the normal media and at high levels in parts of the atheromatous intima. Highest levels of this matrix-associated protein were found in lipid-rich areas of the plaque. The pattern of expression of these two genes contrasted markedly with that of calponin and SM22 alpha, genes expressed predominantly by differentiated smooth muscle cells and whose expression was generally confined to the media of the vessel. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and colocalization of both in atheromatous plaques suggest they have an important role in plaque pathogenesis and stability.

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Intracellular protein catabolism and its control during nutrient deprivation and supply.

G E MORTIMORE, A Pösö (1987)

The continuous turnover of intracellular protein and other macromolecules is a basic cellular process that serves, among other functions, to regulate cytoplasmic content and provide amino acids for ongoing oxidative and biosynthetic reactions during nutrient deprivation. The intensity of breakdown and pattern of regulation, though, vary widely among cells. Rat hepatocytes, for example, exhibit high absolute rates of proteolysis and regulatory effects that diminish during starvation, while corresponding responses in skeletal and cardiac muscle move in the opposite direction. It is also becoming apparent that effects of insulin and other acute regulatory agents on muscle breakdown are limited to nonmyofibrillar components. The latter may be sequestered and degraded within autophagic vacuoles, whereas myofibrillar proteins require an initial attack by calcium-dependent proteases in the cytosol. By contrast, most if not all of the breakdown of resident (long-lived) proteins as well as RNA in the hepatocyte can be explained by lysosomal mechanisms. The uptake of cytoplasmic components by lysosomes can be divided into two major categories, macroautophagy and micro- or basal autophagy. The first is induced by amino acid or insulin/serum deprivation. In the hepatocyte, amino acids alone can regulate this process almost instantaneously over two thirds of the full range of proteolysis, 4.5% to 1.5% per hour. Glucagon, cyclic AMP, and beta-agonists also stimulate macroautophagy in hepatocytes but have opposite effects in skeletal and cardiac myocytes. Basal autophagy differs from the macro type in that the cytoplasmic "bite" is smaller and sequestration is not acutely regulated. It is, however, adaptively decreased during starvation in parallel with absolute rates of basal turnover. Since endoplasmic reticulum comprises an appreciable fraction of the vacuolar content, volume sequestration would be compatible with the known heterogeneity of individual protein turnover if some proteins (or altered proteins) selectively bind to membranes. The amino acid control of macroautophagy in the hepatocyte is accomplished by a small group of direct inhibitors (Leu, Tyr/Phe, Gln, Pro, Met, Trp, and His) and the permissive effect of alanine whereas only leucine is involved in myocytes and adipocytes. Of unusual interest is the fact that the inhibitory amino acid group alone evokes responses in perfused livers that are identical to those of a complete plasma mixture at 0.5 and 4 times normal plasma levels but loses effectiveness almost completely at normal concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)

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THE SMOOTH MUSCLE CELL

Russell Ross, Seymour J. Klebanoff (1971)

These studies have examined the ability of smooth muscle cells from developing aorta of the prepubertal rat to utilize amino acids in the synthesis and secretion of connective tissue proteins. Prepubertal rats, previously given either an alcohol carrier or estradiol-17-beta, were each given an intravenous injection of proline-3H. The animals were sacrificed after 15 and 30 min, and 4 hr. Light and electron microscope radioautographs of the aortic smooth muscle and of the myometrial cells demonstrated that the aortic cells, in both groups of animals, and the myometrial cells, in the estrogen-stimulated animals, took up the proline and rapidly secreted it in both collagen and elastic fibers within 4 hr. In contrast, the myometrial cells of the nonstimulated animal took up relatively small amounts of proline and retained most of the amino acid within the cells. Electron microscope radioautographs demonstrated that the organelles involved in this activity were the rough endoplasmic reticulum and Golgi complex together with peripheral elements, presumed to be small vesicles. These studies have demonstrated that the smooth muscle cells of the developing aorta and of the estrogen-stimulated myometrium have a capacity to synthesize and secrete proteins associated with the extracellular connective tissue matrix.

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Author and article information

Journal

Journal ID (publisher-id): JVR

Journal ID (nlm-ta): J Vasc Res

Journal ID (doi): 10.1159/issn.1018-1172

Title: Journal of Vascular Research

Publisher: S. Karger AG

ISSN (Print): 1018-1172

ISSN (Electronic): 1423-0135

Publication date Subscription-year: 2006

Publication date (Print): February 2006

Publication date (Electronic): 16 February 2006

Volume: 43

Issue: 2

Pages: 157-165

Affiliations

^aCenter for Cell and Gene Therapy, and Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Tex., USA; ^bInstitute of Clinical Chemistry and Laboratory Medicine, University of Mainz, Mainz, and ^cDepartment of Internal Medicine II-Cardiology, and ^dDepartment of Cardiac Surgery, University of Ulm, Ulm, Germany

Article

Publisher ID: 90945 Other ID: J Vasc Res 2006;43:157–165

DOI: 10.1159/000090945

PubMed ID: 16407661

SO-VID: 5549facd-3651-475f-82e1-f16a2b340d36

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Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

History

Date received : 19 August 2005

Date accepted : 16 October 2005

Page count

Figures: 6, References: 37, Pages: 9

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Serum Starvation and Growth Factor Receptor Expression in Vascular Smooth Muscle Cells

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Karger: Cardiovascular System

Most cited references 13

High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

Intracellular protein catabolism and its control during nutrient deprivation and supply.

THE SMOOTH MUSCLE CELL

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Cited by 6

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