Developmental regulation of transforming growth factor-beta 1 responses and vascular smooth muscle growth in spontaneously hypertensive rats.

OBJECTIVE

To investigate the developmental regulation of transforming growth factor-beta 1 (TGF-beta 1) action and the expression of TGF-beta receptors in vascular smooth muscle cells (VSMC) isolated from spontaneously hypertensive rats (SHR).

DESIGN

TGF-beta 1 effects on proliferation and expression of TGF-beta receptor subtypes were compared in VSMC prepared from SHR, Wistar-Kyoto (WKY) and Sprague-Dawley rats of different ages.

METHODS

TGF-beta 1 effects on platelet-derived growth factor-BB (PDGF-BB)-stimulated proliferation were examined in VSMC isolated from SHR, WKY and Sprague-Dawley rats aged 1, 4 and 12 weeks, and from renal hypertensive WKY rats. TGF-beta receptors on the surface of VSMC were identified by affinity labelling, followed by immunoprecipitation with TGF-beta receptor antibodies; complexes were then analysed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis.

RESULTS

TGF-beta 1 inhibited by 60-80% PDGF-BB-stimulated proliferation of VSMC from 1-week-old SHR. In 4-week-old SHR, VSMC were resistant to the antiproliferative action of TGF-beta 1, whereas the mitogenic activity of PDGF-BB was increased approximately 150% by TGF-beta 1 in VSMC from 12-week-old SHR. In contrast, TGF-beta 1 inhibited by 10-50% PDGF-BB-stimulated proliferation of VSMC from age-matched WKY and Sprague-Dawley rats. TGF-beta isoforms (TGF-beta 1, -beta 2, -beta 3) all elicited similar growth responses in VSMC from SHR and WKY rats of different ages. Hypertension per se did not alter TGF-beta 1 effects on proliferation, as TGF-beta 1 inhibited by 30-40% growth factor action on VSMC from control, uni-nephrectomized and one-kidney one-clip hypertensive WKY rats. The type I, II and III TGF-beta receptors were expressed on the surface of VSMC isolated from SHR of different ages.

CONCLUSION

Alterations in TGF-beta 1 responses, which become evident in VSMC from 4-week-old SHR and are most prominent at 12 weeks, may be important in the development of vascular hypertrophy in this rat strain.