© 2000 American Heart Association, Inc.
Vascular Biology |
Phenotypic Modulation by Fibronectin Enhances the Angiotensin II–Generating System in Cultured Vascular Smooth Muscle Cells
From the Second Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan.
Correspondence to Noboru Fukuda, MD, Second Department of Internal Medicine, Nihon University School of Medicine, Ooyaguchi-kami 30–1, Itabashi-ku, Tokyo 173-8610, Japan.
Abstract—We previously
demonstrated that homogeneous cultures of vascular smooth
muscle cells (VSMCs) from spontaneously hypertensive rats produce
angiotensin II (Ang II) in response to increases in the
levels of angiotensinogen, cathepsin D, and
angiotensin-converting enzyme (ACE). The change of VSMCs
from the contractile to the synthetic phenotype increased the
amount of synthetic organelles, resulting in the production of
proteases and growth factors. To evaluate the contribution of the
synthetic phenotype to the generation of Ang II, we examined
the effect of fibronectin (FN), which reportedly induces the synthetic
phenotype, on the Ang II–generating system in VSMCs. Cultured
VSMCs from Wistar-Kyoto rats were incubated with an active fragment of
FN, Arg-Gly-Asp-Ser, for 24, 48, or 72 hours after synchronization of
the cell cycle with 0.2% calf serum for 48 hours.
Immunofluorescence and protein levels of 
-smooth
muscle (SM) actin and expression of SM22 mRNA, apparent in the
contractile phenotype, were suppressed by FN, whereas
expression of matrix Gla mRNA and osteopontin mRNA and protein,
apparent in the synthetic phenotype, was increased. FN (1 to
1000 µg/mL) dose-dependently increased DNA synthesis in the VSMCs,
which was inhibited by the Ang II type 1 receptor
antagonist CV-11974. Ang II–like immunoreactivity as
determined by radioimmunoassay was significantly increased in
conditioned medium from the VSMCs. In addition, mRNA for the Ang
II–generating proteases cathepsin D and ACE was increased by FN.
Expression of transforming growth factor-ß1, platelet-derived
growth factor A-chain, and basic fibroblast growth factor mRNAs was
also increased by FN. These results indicate that the changes
accompanying the alteration to the synthetic phenotype in
homogeneous cultures of VSMCs increase expression of
proteases such as cathepsin D and ACE, which then produce Ang II, and
that these changes increase expression of growth factors that then
induce growth of VSMCs.
Key Words: angiotensin II • vascular smooth muscle • phenotype • rats • reverse transcription–polymerase chain reaction
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