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      Stretch-Induced Collagen Synthesis in Cultured Smooth Muscle Cells from Rabbit Aortic Media and a Possible Involvement of Angiotensin II and Transforming Growth Factor-β


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          Mechanical strain reportedly stimulates the synthesis of collagen in vascular smooth muscle cells (SMCs). The present study was designed to investigate a possible involvement of angiotensin II (Ang II) and transforming growth factor (TGF)-β in stretch-induced collagen synthesis of cultured SMCs derived from the rabbit aortic media. SMCs were cyclically stretched at a rate of 10% elongation and 30 cycles/min for 24 h using the Flexercell<sup>®</sup> strain unit (Flexcell International Corp., McKeesport, Pa.). A two-fold increase in collagen synthesis and a concurrent increase in total protein synthesis were noted in stretched SMCs. Concentration of immunoreactive Ang II in the conditioned medium was elevated under the mechanical strain. Stretch-induced collagen and total protein synthesis were inhibited by either a selective antagonist to Ang II (saralasin), an angiotensin I-converting enzyme inhibitor (captopril) or an antisense oligonucleotide for angiotensinogen mRNA. An elevated secretion of TGF-β, both active and latent forms, was found in the medium of stretched SMCs. Saralasin inhibited the stretch-induced secretion of TGF-β from SMCs. Stretch-induced collagen and total protein synthesis was further inhibited by either an anti-TGF-β1 neutralizing antibody or an adenovirus-mediated transfer of a truncated TGF-β type II receptor. Elevated expression of collagen α1(III) chain and TGF-β1 mRNAs, and its reversal by saralasin were also demonstrated in stretched SMCs. Results indicate that the stretch-induced collagen and total protein synthesis appears to be mediated via an autocrine-paracrine mechanism of Ang II and TGF-β released from SMCs.

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          Most cited references 6

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          Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro.

          Hypertrophy is a fundamental adaptive process employed by postmitotic cardiac and skeletal muscle in response to mechanical load. How muscle cells convert mechanical stimuli into growth signals has been a long-standing question. Using an in vitro model of load (stretch)-induced cardiac hypertrophy, we demonstrate that mechanical stretch causes release of angiotensin II (Ang II) from cardiac myocytes and that Ang II acts as an initial mediator of the stretch-induced hypertrophic response. The results not only provide direct evidence for the autocrine mechanism in load-induced growth of cardiac muscle cells, but also define the pathophysiological role of the local (cardiac) renin-angiotensin system.
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            TGF-beta induces bimodal proliferation of connective tissue cells via complex control of an autocrine PDGF loop.

            Transforming growth factor-beta (TGF-beta) acts as a growth inhibitor, yet it can stimulate proliferation; 1-2 fg/cell of TGF-beta 1 elicits maximal proliferation of dense and sparse cultured smooth muscle cells (SMCs), whereas higher amounts are less stimulatory. This bimodal response is not limited to SMCs, as TGF-beta induces a similar response in human fibroblasts and chondrocytes. The amount of TGF-beta 1 per cell that induces maximal proliferation is identical for dense and sparse SMCs. At low concentrations of TGF-beta, there is a 10-12 hr delay in DNA synthesis compared with that elicited by PDGF. PDGF-AA is detected in the culture medium at 24 hr, and anti-PDGF IgG blocks DNA synthesis. At higher concentrations, TGF-beta 1 decreases transcripts and expression of PDGF receptor alpha subunits. Hence, TGF-beta induces proliferation of connective tissue cells at low concentrations by stimulating autocrine PDGF-AA secretion, which at higher concentrations of TGF-beta, is decreased by down-regulation of PDGF receptor alpha subunits and perhaps by direct growth inhibition.
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              Expression of smooth muscle-specific alpha-isoactin in cultured vascular smooth muscle cells: relationship between growth and cytodifferentiation

              The relationship between growth and cytodifferentiation was studied in cultured rat aortic smooth muscle cells (SMCs) using expression of the smooth muscle (SM)-specific isoactins (Vanderkerckhove, J., and K. Weber, 1979, Differentiation, 14:123-133) as a marker for differentiation in these cells. Isoactin expression was evaluated by: (a) measurements of fractional isoactin content and synthesis ([35S]methionine incorporation) by densitometric evaluation of two- dimensional isoelectric focusing sodium dodecyl sulfate gels, and (b) immunocytological examination using SM-specific isoactin antibodies. Results showed the following: (a) Loss of alpha-SM isoactin was not a prerequisite for initiation of cellular proliferation in primary cultures of rat aortic SMCs. (b) alpha-SM isoactin synthesis and content were low in subconfluent log phase growth cells but increased nearly threefold in density-arrested postconfluent cells. Conversely, beta-nonmuscle actin synthesis and content were higher in rapidly dividing subconfluent cultures than in quiescent postconfluent cultures. These changes were observed in primary and subpassaged cultures. (c) alpha-SM actin synthesis was increased by growth arrest of sparse cultures in serum-free medium (SFM; Libby, P., and K. V. O'Brien, 1983, J. Cell. Physiol., 115:217-223) but reached levels equivalent to density-arrested cells only after extended periods in SFM (i.e., greater than 5 d). (d) SFM did not further augment alpha-SM actin synthesis in postconfluent SMC cultures. (e) Serum stimulation of cells that had been growth-arrested in SFM resulted in a dramatic decrease in alpha-SM actin synthesis that preceded the onset of cellular proliferation. These findings demonstrate that cultured vascular SMCs undergo differential expression of isoactins in relation to their growth state and indicate that growth arrest promotes cytodifferentiation in these cells.

                Author and article information

                J Vasc Res
                Journal of Vascular Research
                S. Karger AG
                April 1998
                16 April 1998
                : 35
                : 2
                : 93-103
                a First Department of Pathology, Wakayama Medical College, Wakayama, and b Molecular Cardiology Unit, Research Institute of Angiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka, Japan
                25570 J Vasc Res 1998;35:93–103
                © 1998 S. Karger AG, Basel

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                Page count
                Figures: 9, References: 58, Pages: 11
                Research Paper


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